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  • 1.
    Boija, Ann
    et al.
    Dept. of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden.
    Holmqvist, Per-Henrik
    Dept. of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden.
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå, Sweden.
    Zare, Aman
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå, Sweden.
    Meyers, David J.
    Dept. Pharmacology and Molecular Sciences, The Johns Hopkins University, School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
    Cole, Philip A.
    Dept. Pharmacology and Molecular Sciences, The Johns Hopkins University, School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Division of CBRN Defence and Security, FOI, Swedish Defence Research Agency, Sweden.
    Mannervik, Mattias
    Dept. of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, SwedenDept. Pharmacology and Molecular Sciences, The Johns Hopkins University, School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
    Drosophila CBP cooperates with GAGA factor to induce high levels of Pol II promoter-proximal pausingManuscript (preprint) (Other academic)
  • 2. Boija, Ann
    et al.
    Mahat, Dig Bijay
    Zare, Aman
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Holmqvist, Per-Henrik
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Meyers, David J
    Cole, Philip A
    Lis, John T
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Mannervik, Mattias
    CBP Regulates Recruitment and Release of Promoter-Proximal RNA Polymerase II2017In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 68, no 3, p. 491-503.e5Article in journal (Refereed)
    Abstract [en]

    Transcription activation involves RNA polymerase II (Pol II) recruitment and release from the promoter into productive elongation, but how specific chromatin regulators control these steps is unclear. Here, we identify a novel activity of the histone acetyltransferase p300/CREB-binding protein (CBP) in regulating promoter-proximal paused Pol II. We find that Drosophila CBP inhibition results in "dribbling" of Pol II from the pause site to positions further downstream but impedes transcription through the +1 nucleosome genome-wide. Promoters strongly occupied by CBP and GAGA factor have high levels of paused Pol II, a unique chromatin signature, and are highly expressed regardless of cell type. Interestingly, CBP activity is rate limiting for Pol II recruitment to these highly paused promoters through an interaction with TFIIB but for transit into elongation by histone acetylation at other genes. Thus, CBP directly stimulates both Pol II recruitment and the ability to traverse the first nucleosome, thereby promoting transcription of most genes.

  • 3.
    Cameron, Sarina R.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nandi, Soumyadeep
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kahn, Tatyana G.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Barrasa, Juan I.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Stenberg, Per
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Division of Chemical, Biological, Radioactive and Nuclear (CBRN) Security and Defence, FOI–Swedish Defence Research Agency, 906 21 Umeå Sweden.
    Schwartz, Yuri B.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    PTE, a novel module to target Polycomb Repressive Complex 1 to the human cyclin D2 (CCND2) oncogene2018In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 293, no 37, p. 14342-14358Article in journal (Refereed)
    Abstract [en]

    Polycomb group proteins are essential epigenetic repressors. They form multiple protein complexes of which two kinds, PRC1 and PRC2, are indispensable for repression. Although much is known about their biochemical properties, how mammalian PRC1 and PRC2 are targeted to specific genes is poorly understood. Here, we establish the cyclin D2 (CCND2) oncogene as a simple model to address this question. We provide the evidence that the targeting of PRC1 to CCND2 involves a dedicated PRC1-targeting element (PTE). The PTE appears to act in concert with an adjacent cytosine-phosphate-guanine (CpG) island to arrange for the robust binding of PRC1 and PRC2 to repressed CCND2. Our findings pave the way to identify sequence-specific DNA-binding proteins implicated in the targeting of mammalian PRC1 complexes and provide novel link between polycomb repression and cancer.

  • 4.
    Figueiredo, Margarida L. A.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Kim, Maria
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå University, SE-90187 Umeå, Sweden.
    Allgardsson, Anders
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Division of CBRN Defence and Security, FOI, Swedish Defence Research Agency, Sweden.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå UniversityUmeå, Sweden; Division of CBRN Defence and Security, FOI, Swedish Defence Research Agency, Sweden.
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Non-coding roX RNAs prevent the binding of the MSL-complex to heterochromatic regions2014In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 12, p. e1004865-Article in journal (Refereed)
    Abstract [en]

    Long non-coding RNAs contribute to dosage compensation in both mammals and Drosophila by inducing changes in the chromatin structure of the X-chromosome. In Drosophila melanogaster, roX1 and roX2 are long non-coding RNAs that together with proteins form the male-specific lethal (MSL) complex, which coats the entire male X-chromosome and mediates dosage compensation by increasing its transcriptional output. Studies on polytene chromosomes have demonstrated that when both roX1 and roX2 are absent, the MSL-complex becomes less abundant on the male X-chromosome and is relocated to the chromocenter and the 4thchromosome. Here we address the role of roX RNAs in MSL-complex targeting and the evolution of dosage compensation in Drosophila. We performed ChIP-seq experiments which showed that MSL-complex recruitment to high affinity sites (HAS) on the X-chromosome is independent of roX and that the HAS sequence motif is conserved in D. simulans. Additionally, a complete and enzymatically active MSL-complex is recruited to six specific genes on the 4thchromosome. Interestingly, our sequence analysis showed that in the absence of roX RNAs, the MSL-complex has an affinity for regions enriched in Hoppel transposable elements and repeats in general. We hypothesize that roX mutants reveal the ancient targeting of the MSL-complex and propose that the role of roX RNAs is to prevent the binding of the MSL-complex to heterochromatin.

  • 5.
    Figueiredo, Margarida L A
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    HP1a Recruitment to Promoters Is Independent of H3K9 Methylation in Drosophila melanogaster2012In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 11, p. e1003061-Article in journal (Refereed)
    Abstract [en]

    Heterochromatin protein 1 (HP1) proteins, recognized readers of the heterochromatin mark methylation of histone H3 lysine 9 (H3K9me), are important regulators of heterochromatin-mediated gene silencing and chromosome structure. In Drosophila melanogaster three histone lysine methyl transferases (HKMTs) are associated with the methylation of H3K9: Su(var)3-9, Setdb1, and G9a. To probe the dependence of HP1a binding on H3K9me, its dependence on these three HKMTs, and the division of labor between the HKMTs, we have examined correlations between HP1a binding and H3K9me patterns in wild type and null mutants of these HKMTs. We show here that Su(var)3-9 controls H3K9me-dependent binding of HP1a in pericentromeric regions, while Setdb1 controls it in cytological region 2L:31 and (together with POF) in chromosome 4. HP1a binds to the promoters and within bodies of active genes in these three regions. More importantly, however, HP1a binding at promoters of active genes is independent of H3K9me and POF. Rather, it is associated with heterochromatin protein 2 (HP2) and open chromatin. Our results support a hypothesis in which HP1a nucleates with high affinity independently of H3K9me in promoters of active genes and then spreads via H3K9 methylation and transient looping contacts with those H3K9me target sites.

  • 6.
    Holmqvist, Per-Henrik
    et al.
    The Wenner-Gren Institute, Developmental Biology, Stockholm University, Stockholm.
    Boija, Ann
    The Wenner-Gren Institute, Developmental Biology, Stockholm University, Stockholm.
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Crona, Filip
    The Wenner-Gren Institute, Developmental Biology, Stockholm University, Stockholm.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Mannervik, Mattias
    The Wenner-Gren Institute, Developmental Biology, Stockholm University, Stockholm.
    Preferential Genome Targeting of the CBP Co-Activator by Rel and Smad Proteins in Early Drosophila melanogaster Embryos2012In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 6, p. e1002769-Article in journal (Refereed)
    Abstract [en]

    CBP and the related p300 protein are widely used transcriptional co-activators in metazoans that interact with multiple transcription factors. Whether CBP/p300 occupies the genome equally with all factors or preferentially binds together with some factors is not known. We therefore compared Drosophila melanogaster CBP (nejire) ChIP-seq peaks with regions bound by 40 different transcription factors in early embryos, and we found high co-occupancy with the Rel-family protein Dorsal. Dorsal is required for CBP occupancy in the embryo, but only at regions where few other factors are present. CBP peaks in mutant embryos lacking nuclear Dorsal are best correlated with TGF-ß/Dpp-signaling and Smad-protein binding. Differences in CBP occupancy in mutant embryos reflect gene expression changes genome-wide, but CBP also occupies some non-expressed genes. The presence of CBP at silent genes does not result in histone acetylation. We find that Polycomb-repressed H3K27me3 chromatin does not preclude CBP binding, but restricts histone acetylation at CBP-bound genomic sites. We conclude that CBP occupancy in Drosophila embryos preferentially overlaps factors controlling dorso-ventral patterning and that CBP binds silent genes without causing histone hyperacetylation.

  • 7. Hägglund, Moa
    et al.
    Bäckman, Stina
    Macellaro, Anna
    Lindgren, Fetter
    Borgmästars, Emmy
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Jacobsson, Karin
    Dryselius, Rikard
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Division of CBRN Security and Defence, FOI, Swedish Defence Research Agency, Umeå, Sweden.
    Sjödin, Andreas
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Division of CBRN Security and Defence, FOI, Swedish Defence Research Agency, Umeå, Sweden.
    Forsman, Mats
    Ahlinder, Jon
    Accounting for bacterial overlap between raw water communities and contaminating sources improves the accuracy of signature-based microbial source tracking2018In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 9, article id 2364Article in journal (Refereed)
    Abstract [en]

    Microbial source tracking (MST) analysis is essential to identifying and mitigating the fecal pollution of water resources. The signature-based MST method uses a library of sequences to identify contaminants based on operational taxonomic units (OTUs) that are unique to a certain source. However, no clear guidelines for how to incorporate OTU overlap or natural variation in the raw water bacterial community into MST analyses exist. We investigated how the inclusion of bacterial overlap between sources in the library affects source prediction accuracy. To achieve this, large-scale sampling-including feces from seven species, raw sewage, and raw water samples from water treatment plants - was followed by 16S rRNA amplicon sequencing. The MST library was defined using three settings: (i) no raw water communities represented; (ii) raw water communities selected through clustering analysis; and (iii) local water communities collected across consecutive years. The results suggest that incorporating either the local background or representative bacterial composition improves MST analyses, as the results were positively correlated to measured levels of fecal indicator bacteria and the accuracy at which OTUs were assigned to the correct contamination source increased fourfold. Using the proportion of OTUs with high source origin probability, underpinning a contaminating signal, is a solid foundation in a framework for further deciphering and comparing contaminating signals derived in signature-based MST approaches. In conclusion, incorporating background bacterial composition of water in MST can improve mitigation efforts for minimizing the spread of pathogenic and antibiotic resistant bacteria into essential freshwater resources.

  • 8.
    Johansson, Anna-Mia
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Allgardsson, Anders
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    msl2 mRNA is bound by free nuclear MSL complex in Drosophila melanogaster2011In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 39, no 15, p. 6428-6439Article in journal (Refereed)
    Abstract [en]

    In Drosophila, the global increase in transcription from the male X chromosome to compensate for its monosomy is mediated by the male-specific lethal (MSL) complex consisting of five proteins and two non-coding RNAs, roX1 and roX2. After an initial sequence-dependent recognition by the MSL complex of 150-300 high affinity sites, the spread to the majority of the X-linked genes depends on local MSL-complex concentration and active transcription. We have explored whether any additional RNA species are associated with the MSL complex. No additional roX RNA species were found, but a strong association was found between a spliced and poly-adenylated msl2 RNA and the MSL complex. Based on our results, we propose a model in which a non-chromatin-associated partial or complete MSL-complex titrates newly transcribed msl2 mRNA and thus regulates the amount of available MSL complex by feedback. This represents a novel mechanism in chromatin structure regulation.

  • 9.
    Johansson, Anna-Mia
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Allgardsson, Anders
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    POF Regulates the Expression of Genes on the Fourth Chromosome in Drosophila melanogaster by Binding to Nascent RNA2012In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 32, no 11, p. 2121-2134Article in journal (Other academic)
    Abstract [en]

    In Drosophila, two chromosome-wide compensatory systems have been characterized: the dosage compensation system that acts on the male X chromosome and the chromosome-specific regulation of genes located on the heterochromatic fourth chromosome. Dosage compensation in Drosophila is accomplished by hypertranscription of the single male X chromosome mediated by the male-specific lethal (MSL) complex. The mechanism of this compensation is suggested to involve enhanced transcriptional elongation mediated by the MSL complex, while the mechanism of compensation mediated by the painting of fourth (POF) protein on the fourth chromosome has remained elusive. Here, we show that POF binds to nascent RNA, and this binding is associated with increased transcription output from chromosome 4. We also show that genes located in heterochromatic regions spend less time in transition from the site of transcription to the nuclear envelope. These results provide useful insights into the means by which genes in heterochromatic regions can overcome the repressive influence of their hostile environment.

  • 10.
    Johansson, Anna-Mia
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Science and Technology).
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Science and Technology).
    Bernhardsson, Carolina
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Science and Technology).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Science and Technology).
    Painting of fourth and chromosome-wide regulation of the 4th chromosome in Drosophila melanogaster.2007In: EMBO J, ISSN 0261-4189, Vol. 26, no 9, p. 2307-2316Article in journal (Refereed)
    Abstract [en]

    Drosophila melanogaster exhibits two expression-regulating systems that target whole, specific chromosomes: the dosage compensation system whereby the male-specific lethal complex doubles transcription of genes on the male X-chromosome and the chromosome 4-specific protein Painting of fourth, POF. POF is the first example of an autosome-specific protein and its presence raises the question of the universality of chromosome-specific regulation. Here we show that POF and heterochromatin protein 1 (HP1) are involved in the global regulation of the 4th chromosome. Contrary to previous conclusions, Pof is not essential for survival of diplo-4th karyotype flies. However, Pof is essential for survival of haplo-4th individuals and expression of chromosome 4 genes in diplo-4th individuals is decreased in the absence of Pof. Mapping of POF using chromatin immunoprecipitation suggested that it binds within genes. Furthermore, we show that POF binding is dependent on heterochromatin and that POF and HP1 bind interdependently to the 4th chromosome. We propose a balancing mechanism involving POF and HP1 that provides a feedback system for fine-tuning expression status of genes on the 4th chromosome.

  • 11.
    Johansson, Anna-Mia
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP).
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Science and Technology).
    Pettersson, Fredrik
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Science and Technology).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Science and Technology).
    POF and HP1 bind expressed exons, suggesting a balancing mechanism for gene regulation2007In: PLoS Genet, ISSN 1553-7404, Vol. 3, no 11, p. e209-Article in journal (Refereed)
    Abstract [en]

    Two specific chromosome-targeting and gene regulatory systems are present in Drosophila melanogaster. The male X chromosome is targeted by the male-specific lethal complex believed to mediate the 2-fold up-regulation of the X-linked genes, and the highly heterochromatic fourth chromosome is specifically targeted by the Painting of Fourth (POF) protein, which, together with heterochromatin protein 1 (HP1), modulates the expression level of genes on the fourth chromosome. Here we use chromatin immunoprecipitation and tiling microarray analysis to map POF and HP1 on the fourth chromosome in S2 cells and salivary glands at high resolution. The enrichment profiles were complemented by transcript profiles to examine the link between binding and transcripts. The results show that POF specifically binds to genes, with a strong preference for exons, and the HP1 binding profile is a mirror image of POF, although HP1 displays an additional "peak" in the promoter regions of bound genes. HP1 binding within genes is much higher than the basal HP1 enrichment on Chromosome 4. Our results suggest a balancing mechanism for the regulation of the fourth chromosome where POF and HP1 competitively bind at increasing levels with increased transcriptional activity. In addition, our results contradict transposable elements as a major nucleation site for HP1 on the fourth chromosome.

  • 12.
    Kahn, Tatyana G.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Dorafshan, Eshagh
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Schultheis, Dorothea
    Zare, Aman
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Division of CBRN Defense and Security, Swedish Defense Research Agency, FOI, Umea, 906 21, Sweden.
    Reim, Ingolf
    Pirrotta, Vincenzo
    Schwartz, Yuri B.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Interdependence of PRC1 and PRC2 for recruitment to Polycomb Response Elements2016In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 44, no 21, p. 10132-10149Article in journal (Refereed)
    Abstract [en]

    Polycomb Group (PcG) proteins are epigenetic repressors essential for control of development and cell differentiation. They form multiple complexes of which PRC1 and PRC2 are evolutionary conserved and obligatory for repression. The targeting of PRC1 and PRC2 is poorly understood and was proposed to be hierarchical and involve tri-methylation of histone H3 (H3K27me3) and/or monoubiquitylation of histone H2A (H2AK118ub). Here, we present a strict test of this hypothesis using the Drosophila model. We discover that neither H3K27me3 nor H2AK118ub is required for targeting PRC complexes to Polycomb Response Elements (PREs). We find that PRC1 can bind PREs in the absence of PRC2 but at many PREs PRC2 requires PRC1 to be targeted. We show that one role of H3K27me3 is to allow PcG complexes anchored at PREs to interact with surrounding chromatin. In contrast, the bulk of H2AK118ub is unrelated to PcG repression. These findings radically change our view of how PcG repression is targeted and suggest that PRC1 and PRC2 can communicate independently of histone modifications.

  • 13.
    Kahn, Tatyana G.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, USA.
    Stenberg, Per
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Pirrotta, Vincenzo
    Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, USA.
    Schwartz, Yuri B.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, USA.
    Combinatorial Interactions Are Required for the Efficient Recruitment of Pho Repressive Complex (PhoRC) to Polycomb Response Elements2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 7, p. e1004495-Article in journal (Refereed)
    Abstract [en]

    Polycomb Group (PcG) proteins are epigenetic repressors that control metazoan development and cell differentiation. In Drosophila, PcG proteins form five distinct complexes targeted to genes by Polycomb Response Elements (PREs). Of all PcG complexes PhoRC is the only one that contains a sequence-specific DNA binding subunit (PHO or PHOL), which led to a model that places PhoRC at the base of the recruitment hierarchy. Here we demonstrate that in vivo PHO is preferred to PHOL as a subunit of PhoRC and that PHO and PHOL associate with PREs and a subset of transcriptionally active promoters. Although the binding to the promoter sites depends on the quality of recognition sequences, the binding to PREs does not. Instead, the efficient recruitment of PhoRC to PREs requires the SFMBT subunit and crosstalk with Polycomb Repressive Complex 1. We find that human YY1 protein, the ortholog of PHO, binds sites at active promoters in the human genome but does not bind most PcG target genes, presumably because the interactions involved in the targeting to Drosophila PREs are lost in the mammalian lineage. We conclude that the recruitment of PhoRC to PREs is based on combinatorial interactions and propose that such a recruitment strategy is important to attenuate the binding of PcG proteins when the target genes are transcriptionally active. Our findings allow the appropriate placement of PhoRC in the PcG recruitment hierarchy and provide a rationale to explain why YY1 is unlikely to serve as a general recruiter of mammalian Polycomb complexes despite its reported ability to participate in PcG repression in flies.

  • 14. Karlsson, E.
    et al.
    Larkeryd, A.
    Sjödin, Andreas
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Swedish Defence Research Agency, Umeå, Sweden.
    Forsman, M.
    Stenberg, Per
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Swedish Defence Research Agency, Umeå, Sweden; Department of Chemistry, Computational Life Science Cluster (CLiC), Umeå University, Umeå, Sweden.
    Scaffolding of a bacterial genome using MinION nanopore sequencing2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 11996Article in journal (Refereed)
    Abstract [en]

    Second generation sequencing has revolutionized genomic studies. However, most genomes contain repeated DNA elements that are longer than the read lengths achievable with typical sequencers, so the genomic order of several generated contigs cannot be easily resolved. A new generation of sequencers offering substantially longer reads is emerging, notably the Pacific Biosciences (PacBio) RS II system and the MinION system, released in early 2014 by Oxford Nanopore Technologies through an early access program. The latter has highly advantageous portability and sequences samples by measuring changes in ionic current when single-stranded DNA molecules are translocated through nanopores. We show that the MinION system produces long reads with high mapability that can be used for scaffolding bacterial genomes, despite currently producing substantially higher error rates than PacBio reads. With further development we anticipate that MinION will be useful not only for assembling genomes, but also for rapid detection of organisms, potentially in the field.

  • 15.
    Kumar, Rajendra
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Lizana, Ludvig
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Division of CBRN Security and Defence, FOI-Swedish Defence Research Agency, Umeå, Sweden.
    Genomic 3D compartments emerge from unfolding mitotic chromosomes2019In: Chromosoma, ISSN 0009-5915, E-ISSN 1432-0886, Vol. 128, no 1, p. 15-20Article in journal (Refereed)
    Abstract [en]

    The 3D organisation of the genome in interphase cells is not a randomly folded polymer. Rather, experiments show that chromosomes arrange into a network of 3D compartments that correlate with biological processes, such as transcription, chromatin modifications and protein binding. However, these compartments do not exist during cell division when the DNA is condensed, and it is unclear how and when they emerge. In this paper, we focus on the early stages after cell division as the chromosomes start to decondense. We use a simple polymer model to understand the types of 3D structures that emerge from local unfolding of a compact initial state. From simulations, we recover 3D compartments, such as TADs and A/B compartments that are consistently detected in chromosome capture experiments across cell types and organisms. This suggests that the large-scale 3D organisation is a result of an inflation process.

  • 16.
    Kumar, Rajendra
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Sobhy, Haitham
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). FOI Swedish Def Res Agcy, Div CBRN Secur & Def, S-90621 Umea, Sweden.
    Lizana, Ludvig
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Genome contact map explorer: a platform for the comparison, interactive visualization and analysis of genome contact maps2017In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 17, article id e152Article in journal (Refereed)
    Abstract [en]

    Hi-C experiments generate data in form of large genome contact maps (Hi-C maps). These show that chromosomes are arranged in a hierarchy of three-dimensional compartments. But to understand how these compartments form and by how much they affect genetic processes such as gene regulation, biologists and bioinformaticians need efficient tools to visualize and analyze Hi-C data. However, this is technically challenging because these maps are big. In this paper, we remedied this problem, partly by implementing an efficient file format and developed the genome contact map explorer platform. Apart from tools to process Hi-C data, such as normalization methods and a programmable interface, we made a graphical interface that let users browse, scroll and zoom Hi-C maps to visually search for patterns in the Hi-C data. In the software, it is also possible to browse several maps simultaneously and plot related genomic data. The software is openly accessible to the scientific community.

  • 17.
    Landfors, Mattias
    et al.
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Normalization of high dimensional genomics data where the distribution of the altered variables is skewed2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 11, p. e27942-Article in journal (Refereed)
    Abstract [en]

    Genome-wide analysis of gene expression or protein binding patterns using different array or sequencing based technologies is now routinely performed to compare different populations, such as treatment and reference groups. It is often necessary to normalize the data obtained to remove technical variation introduced in the course of conducting experimental work, but standard normalization techniques are not capable of eliminating technical bias in cases where the distribution of the truly altered variables is skewed, i.e. when a large fraction of the variables are either positively or negatively affected by the treatment. However, several experiments are likely to generate such skewed distributions, including ChIP-chip experiments for the study of chromatin, gene expression experiments for the study of apoptosis, and SNP-studies of copy number variation in normal and tumour tissues. A preliminary study using spike-in array data established that the capacity of an experiment to identify altered variables and generate unbiased estimates of the fold change decreases as the fraction of altered variables and the skewness increases. We propose the following work-flow for analyzing high-dimensional experiments with regions of altered variables: (1) Pre-process raw data using one of the standard normalization techniques. (2) Investigate if the distribution of the altered variables is skewed. (3) If the distribution is not believed to be skewed, no additional normalization is needed. Otherwise, re-normalize the data using a novel HMM-assisted normalization procedure. (4) Perform downstream analysis. Here, ChIP-chip data and simulated data were used to evaluate the performance of the work-flow. It was found that skewed distributions can be detected by using the novel DSE-test (Detection of Skewed Experiments). Furthermore, applying the HMM-assisted normalization to experiments where the distribution of the truly altered variables is skewed results in considerably higher sensitivity and lower bias than can be attained using standard and invariant normalization methods.

  • 18.
    Larsson, Jan
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP).
    Svensson, Malin J
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP).
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP).
    Mäkitalo, Maria
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP).
    Painting of fourth in genus Drosophila suggests autosome-specific gene regulation2004In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, no 26, p. 9728-9733Article in journal (Refereed)
    Abstract [en]

    Painting of fourth (POF) is a chromosome-specific protein in Drosophila and represents the first example of an autosome-specific protein. POF binds to chromosome 4 in Drosophila melanogaster, initiating at the proximal region, followed by a spreading dependent on chromosome 4-specific sequences or structures. Chromosome-specific gene regulation is known thus far only as a mechanism to equalize the transcriptional activity of the single male X chromosome with that of the two female X chromosomes. In Drosophila, a complex including the male-specific lethal proteins, "paints" the male X chromosome, mediating its hypertranscription, explained to some extent by the acetylation of lysine 16 on histone H4. Here, we show that Pof is essential for viability in both sexes and for female fertility. POF binding to an autosome, the F element, is conserved in genus Drosophila, indicating functional conservation of the autosome specificity. In three of nine studied species, POF binds to the male X chromosome. When bound to the male X, it also colocalizes with the dosage compensation protein male-specific lethal 3, suggesting a relationship to dosage compensation. The chromosome specificity is determined at the species level and not by the amino acid sequence. We argue that POF is involved in a chromosome-specific regulatory function.

  • 19. Lee, Sang Hoon
    et al.
    Kim, Yeonghoon
    Lee, Sungmin
    Durang, Xavier
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Jeon, Jae-Hyung
    Lizana, Ludvig
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Mapping the spectrum of 3D communities in human chromosome conformation capture data2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 6859Article in journal (Refereed)
    Abstract [en]

    Several experiments show that the three dimensional (3D) organization of chromosomes affects genetic processes such as transcription and gene regulation. To better understand this connection, researchers developed the Hi-C method that is able to detect the pairwise physical contacts of all chromosomal loci. The Hi-C data show that chromosomes are composed of 3D compartments that range over a variety of scales. However, it is challenging to systematically detect these cross-scale structures. Most studies have therefore designed methods for specific scales to study foremost topologically associated domains (TADs) and A/B compartments. To go beyond this limitation, we tailor a network community detection method that finds communities in compact fractal globule polymer systems. Our method allows us to continuously scan through all scales with a single resolution parameter. We found: (i) polymer segments belonging to the same 3D community do not have to be in consecutive order along the polymer chain. In other words, several TADs may belong to the same 3D community. (ii) CTCF proteins-a loop-stabilizing protein that is ascribed a big role in TAD formation-are well correlated with community borders only at one level of organization. (iii) TADs and A/B compartments are traditionally treated as two weakly related 3D structures and detected with different algorithms. With our method, we detect both by simply adjusting the resolution parameter. We therefore argue that they represent two specific levels of a continuous spectrum 3D communities, rather than seeing them as different structural entities.

  • 20.
    Lundberg, Lina E
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Figueiredo, Margarida L A
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Buffering and proteolysis are induced by segmental monosomy in Drosophila melanogaster2012In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 40, no 13, p. 5926-5937Article in journal (Refereed)
    Abstract [en]

    Variation in the number of individual chromosomes (chromosomal aneuploidy) or chromosome segments (segmental aneuploidy) is associated with developmental abnormalities and reduced fitness in all species examined; it is the leading cause of miscarriages and mental retardation and a hallmark of cancer. However, despite their documented importance in disease, the effects of aneuploidies on the transcriptome remain largely unknown. We have examined the expression effects of seven heterozygous chromosomal deficiencies, both singly and in all pairwise combinations, in Drosophila melanogaster. The results show that genes in one copy are buffered, i.e. expressed more strongly than the expected 50% of wild-type level, the buffering is general and not influenced by other monosomic regions. Furthermore, long genes are significantly more highly buffered than short genes and gene length appears to be the primary determinant of the buffering degree. For short genes the degree of buffering depends on expression level and expression pattern. Furthermore, the results show that in deficiency heterozygotes the expression of genes involved in proteolysis is enhanced and negatively correlates with the degree of buffering. Thus, enhanced proteolysis appears to be a general response to aneuploidy.

  • 21.
    Lundberg, Lina E
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    HP1a, Su(var)3-9, SETDB1 and POF stimulate or repress gene expression depending on genomic position, gene length and expression pattern in Drosophila melanogaster2013In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 41, no 8, p. 4481-4494Article in journal (Refereed)
    Abstract [en]

    Heterochromatin protein 1a (HP1a) is a chromatin-associated protein important for the formation and maintenance of heterochromatin. In Drosophila, the two histone methyltransferases SETDB1 and Su(var)3-9 mediate H3K9 methylation marks that initiates the establishment and spreading of HP1a-enriched chromatin. Although HP1a is generally regarded as a factor that represses gene transcription, several reports have linked HP1a binding to active genes, and in some cases, it has been shown to stimulate transcriptional activity. To clarify the function of HP1a in transcription regulation and its association with Su(var)3-9, SETDB1 and the chromosome 4-specific protein POF, we conducted genome-wide expression studies and combined the results with available binding data in Drosophila melanogaster. The results suggest that HP1a, SETDB1 and Su(var)3-9 repress genes on chromosome 4, where non-ubiquitously expressed genes are preferentially targeted, and stimulate genes in pericentromeric regions. Further, we showed that on chromosome 4, Su(var)3-9, SETDB1 and HP1a target the same genes. In addition, we found that transposons are repressed by HP1a and Su(var)3-9 and that the binding level and expression effects of HP1a are affected by gene length. Our results indicate that genes have adapted to be properly expressed in their local chromatin environment.

  • 22.
    Philip, Philge
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå University, Sweden.
    Boija, Ann
    Dept. of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden.
    Mannervik, Mattias
    Dept. of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå University, Sweden.
    CBP functions outside of promoters and enhancers in Drosophila melanogasterManuscript (preprint) (Other academic)
  • 23.
    Philip, Philge
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Centre for Cellular and Molecular Biology, Uppal Road, Telangana, India .
    Boija, Ann
    Vaid, Roshan
    Churcher, Allison M
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Meyers, David J
    Cole, Philip A
    Mannervik, Mattias
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Division of CBRN Security and Defence, FOI–Swedish Defence Research Agency, Umeå, Sweden.
    CBP binding outside of promoters and enhancers in Drosophila melanogaster2015In: Epigenetics & Chromatin, ISSN 1756-8935, E-ISSN 1756-8935, Vol. 8, article id 48Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: CREB-binding protein (CBP, also known as nejire) is a transcriptional co-activator that is conserved in metazoans. CBP plays an important role in embryonic development and cell differentiation and mutations in CBP can lead to various diseases in humans. In addition, CBP and the related p300 protein have successfully been used to predict enhancers in both humans and flies when they occur with monomethylation of histone H3 on lysine 4 (H3K4me1).

    RESULTS: Here, we compare CBP chromatin immunoprecipitation sequencing data from Drosophila S2 cells with modENCODE data and show that CBP is bound at genomic sites with a wide range of functions. As expected, we find that CBP is bound at active promoters and enhancers. In addition, we find that the strongest CBP sites in the genome are found at Polycomb response elements embedded in histone H3 lysine 27 trimethylated (H3K27me3) chromatin, where they correlate with binding of the Pho repressive complex. Interestingly, we find that CBP also binds to most insulators in the genome. At a subset of these, CBP may regulate insulating activity, measured as the ability to prevent repressive H3K27 methylation from spreading into adjacent chromatin.

    CONCLUSIONS: We conclude that CBP could be involved in a much wider range of functions than has previously been appreciated, including Polycomb repression and insulator activity. In addition, we discuss the possibility that a common role for CBP at all functional elements may be to regulate interactions between distant chromosomal regions and speculate that CBP is controlling higher order chromatin organization.

  • 24.
    Philip, Philge
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Pettersson, Fredrik
    Umbio, 907 19 Umeå, Sweden.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Sequence signatures involved in targeting the male-specific lethal complex to X-chromosomal genes in Drosophila melanogaster2012In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, p. 97-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In Drosophila melanogaster, the dosage-compensation system that equalizes X-linked gene expression between males and females, thereby assuring that an appropriate balance is maintained between the expression of genes on the X chromosome(s) and the autosomes, is at least partially mediated by the Male-Specific Lethal (MSL) complex. This complex binds to genes with a preference for exons on the male X chromosome with a 3' bias, and it targets most expressed genes on the X chromosome. However, a number of genes are expressed but not targeted by the complex. High affinity sites seem to be responsible for initial recruitment of the complex to the X chromosome, but the targeting to and within individual genes is poorly understood.

    RESULTS: We have extensively examined X chromosome sequence variation within five types of gene features (promoters, 5' UTRs, coding sequences, introns, 3' UTRs) and intergenic sequences, and assessed its potential involvement in dosage compensation. Presented results show that: the X chromosome has a distinct sequence composition within its gene features; some of the detected variation correlates with genes targeted by the MSL-complex; the insulator protein BEAF-32 preferentially binds upstream of MSL-bound genes; BEAF-32 and MOF co-localizes in promoters; and that bound genes have a distinct sequence composition that shows a 3' bias within coding sequence.

    CONCLUSIONS: Although, many strongly bound genes are close to a high affinity site neither our promoter motif nor our coding sequence signatures show any correlation to HAS. Based on the results presented here, we believe that there are sequences in the promoters and coding sequences of targeted genes that have the potential to direct the secondary spreading of the MSL-complex to nearby genes.

  • 25.
    Philip, Philge
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Male X-linked genes in Drosophila melanogaster are compensated independently of the Male-Specific Lethal complex2013In: Epigenetics & Chromatin, ISSN 1756-8935, E-ISSN 1756-8935, Vol. 6, no Article number: 35Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In organisms where the two sexes have unequal numbers of X-chromosomes, the expression of X-linked genes needs to be balanced not only between the two sexes, but also between X and the autosomes. In Drosophila melanogaster, the Male-Specific Lethal (MSL) complex is believed to produce a 2-fold increase in expression of genes on the male X, thus restoring this balance.

    RESULTS: Here we show that almost all the genes on the male X are effectively compensated. However, many genes are compensated without any significant recruitment of the MSL-complex. These genes are very weakly, if at all, affected by mutations or RNAi against MSL-complex components. In addition, even the genes that are strongly bound by MSL rely on mechanisms other than the MSL-complex for proper compensation. We find that long, non-ubiquitously expressed genes tend to rely less on the MSL-complex for their compensation and genes that in addition are far from High Affinity Sites tend to not bind the complex at all or very weakly.

    CONCLUSIONS: We conclude that most of the compensation of X-linked genes is produced by an MSL-independent mechanism. Similar to the case of the MSL-mediated compensation we do not yet know the mechanism behind the MSL-independent compensation that appears to act preferentially on long genes. Even if we observe similarities, it remains to be seen if the mechanism is related to the buffering that is observed in autosomal aneuploidies.

  • 26. Schwartz, Yuri B.
    et al.
    Kahn, Tatyana G.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Ohno, Katsuhito
    Bourgon, Richard
    Pirrotta, Vincenzo
    Alternative Epigenetic Chromatin States of Polycomb Target Genes2010In: PLoS Genetics, ISSN 1553-7390, Vol. 6, no 1, p. e1000805-Article in journal (Refereed)
    Abstract [en]

    Polycomb (PcG) regulation has been thought to produce stable long-term gene silencing. Genomic analyses in Drosophila and mammals, however, have shown that it targets many genes, which can switch state during development. Genetic evidence indicates that critical for the active state of PcG target genes are the histone methyltransferases Trithorax (TRX) and ASH1. Here we analyze the repertoire of alternative states in which PcG target genes are found in different Drosophila cell lines and the role of PcG proteins TRX and ASH1 in controlling these states. Using extensive genome-wide chromatin immunoprecipitation analysis, RNAi knockdowns, and quantitative RT-PCR, we show that, in addition to the known repressed state, PcG targets can reside in a transcriptionally active state characterized by formation of an extended domain enriched in ASH1, the N-terminal, but not C-terminal moiety of TRX and H3K27ac. ASH1/TRX N-ter domains and transcription are not incompatible with repressive marks, sometimes resulting in a "balanced" state modulated by both repressors and activators. Often however, loss of PcG repression results instead in a "void" state, lacking transcription, H3K27ac, or binding of TRX or ASH1. We conclude that PcG repression is dynamic, not static, and that the propensity of a target gene to switch states depends on relative levels of PcG, TRX, and activators. N-ter TRX plays a remarkable role that antagonizes PcG repression and preempts H3K27 methylation by acetylation. This role is distinct from that usually attributed to TRX/MLL proteins at the promoter. These results have important implications for Polycomb gene regulation, the "bivalent" chromatin state of embryonic stem cells, and gene expression in development.

  • 27.
    Sjödin, Andreas
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Division of CBRN Defence and Security, Swedish Defence Research Agency, FOI, Umeå, Sweden.
    Öhrman, Caroline
    Division of CBRN Defence and Security, Swedish Defence Research Agency, FOI, Umeå, Sweden.
    Bäckman, Stina
    Division of CBRN Defence and Security, Swedish Defence Research Agency, FOI, Umeå, Sweden.
    Lärkeryd, Adrian
    Division of CBRN Defence and Security, Swedish Defence Research Agency, FOI, Umeå, Sweden.
    Granberg, Malin
    Division of CBRN Defence and Security, Swedish Defence Research Agency, FOI, Umeå, Sweden.
    Lundmark, Eva
    Division of CBRN Defence and Security, Swedish Defence Research Agency, FOI, Umeå, Sweden.
    Karlsson, Edvin
    Division of CBRN Defence and Security, Swedish Defence Research Agency, FOI, Umeå, Sweden.
    Nilsson, Elin
    Division of CBRN Defence and Security, Swedish Defence Research Agency, FOI, Umeå, Sweden.
    Vallesi, Adriana
    cLaboratory of Eukaryotic Microbiology and Animal Biology, University of Camerino, Camerino, Macerata, Italy.
    Tellgren-Roth, Christian
    Uppsala Genome Center, National Genomics Infrastructure-Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, BMC, Uppsala, Sweden.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Thelaus, Johanna
    Division of CBRN Defence and Security, Swedish Defence Research Agency, FOI, Umeå, Sweden.
    Complete Genome Sequence of Francisella endociliophora Strain FSC1006, Isolated from a Laboratory Culture of the Marine Ciliate Euplotes raikovi2014In: Genome Announcements, ISSN 2169-8287, E-ISSN 2169-8287, Vol. 2, no 6, p. 6 e01227-14-Article in journal (Refereed)
    Abstract [en]

    A strain of Francisella endociliophora was isolated from a laboratory culture of the marine ciliate Euplotes raikovi. Here, we report the complete genome sequence of the bacterial strain FSC1006 (Francisella Strain Collection, Swedish Defence Research Agency, Umeå, Sweden).

  • 28.
    Sobhy, Haitham
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Kumar, Rajendra
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Lewerentz, Jacob
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Lizana, Ludvig
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Division of CBRN Security and Defence, FOI–Swedish Defence Research Agency, Umeå, Sweden.
    Highly interacting regions of the human genome are enriched with enhancers and bound by DNA repair proteins2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 4577Article in journal (Refereed)
    Abstract [en]

    In specific cases, chromatin clearly forms long-range loops that place distant regulatory elements in close proximity to transcription start sites, but we have limited understanding of many loops identified by Chromosome Conformation Capture (such as Hi-C) analyses. In efforts to elucidate their characteristics and functions, we have identified highly interacting regions (HIRs) using intra-chromosomal Hi-C datasets with a new computational method based on looking at the eigenvector that corresponds to the smallest eigenvalue (here unity). Analysis of these regions using ENCODE data shows that they are in general enriched in bound factors involved in DNA damage repair and have actively transcribed genes. However, both highly transcribed regions as well as transcriptionally inactive regions can form HIRs. The results also indicate that enhancers and super-enhancers in particular form long-range interactions within the same chromosome. The accumulation of DNA repair factors in most identified HIRs suggests that protection from DNA damage in these regions is essential for avoidance of detrimental rearrangements.

  • 29.
    Stenberg, Per
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå University, Umeå, Sweden.
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Buffering and the evolution of chromosome-wide gene regulation2011In: Chromosoma, ISSN 0009-5915, E-ISSN 1432-0886, Vol. 120, no 3, p. 213-225Article in journal (Refereed)
    Abstract [en]

    Copy number variation (CNV) in terms of aneuploidies of both entire chromosomes and chromosomal segments is an important evolutionary driving force, but it is inevitably accompanied by potentially problematic variations in gene doses and genomic instability. Thus, a delicate balance must be maintained between mechanisms that compensate for variations in gene doses (and thus allow such genomic variability) and selection against destabilizing CNVs. In Drosophila, three known compensatory mechanisms have evolved: a general segmental aneuploidy-buffering system and two chromosome-specific systems. The two chromosome-specific systems are the male-specific lethal complex, which is important for dosage compensation of the male X chromosome, and Painting of fourth, which stimulates expression of the fourth chromosome. In this review, we discuss the origin and function of buffering and compensation using Drosophila as a model.

  • 30.
    Stenberg, Per
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Lundberg, Lina E.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Johansson, Anna-Mia
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Umeå University, Faculty of Social Sciences, Department of Statistics.
    Svensson, Malin J.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Buffering of segmental and chromosomal aneuploidies in Drosophila melanogaster2009In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 5, no 5Article in journal (Refereed)
    Abstract [en]

    Chromosomal instability, which involves the deletion and duplication of chromosomes or chromosome parts, is a common feature of cancers, and deficiency screens are commonly used to detect genes involved in various biological pathways. However, despite their importance, the effects of deficiencies, duplications, and chromosome losses on the regulation of whole chromosomes and large chromosome domains are largely unknown. Therefore, to explore these effects, we examined expression patterns of genes in several Drosophila deficiency hemizygotes and a duplication hemizygote using microarrays. The results indicate that genes expressed in deficiency hemizygotes are significantly buffered, and that the buffering effect is general rather than being mainly mediated by feedback regulation of individual genes. In addition, differentially expressed genes in haploid condition appear to be generally more strongly buffered than ubiquitously expressed genes in haploid condition, but, among genes present in triploid condition, ubiquitously expressed genes are generally more strongly buffered than differentially expressed genes. Furthermore, we show that the 4th chromosome is compensated in response to dose differences. Our results suggest general mechanisms have evolved that stimulate or repress gene expression of aneuploid regions as appropriate, and on the 4th chromosome of Drosophila this compensation is mediated by Painting of Fourth (POF).

  • 31.
    Stenberg, Per
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Lundmark, Magnus
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Distribution, mechanisms and evolutionary significance of clonality and polyploidy in weevils2004In: Agricultural and Forest Entomology, ISSN 1461-9555, E-ISSN 1461-9563, Vol. 6, no 4, p. 259-266Article in journal (Refereed)
    Abstract [en]

    1 Genetical mtDNA relationships of 41 taxa of weevils were examined using cladistics. Ingroup taxa belong to Otiorhynchus scaber and O. nodosus and outgroup comparison was made with O. singularis. All three species are minor forest pests.

    2 Otiorhynchus scaber specimens are either diploid sexuals or diploid, triploid and tetraploid clones, from two different populations (Slovenia and Austria) that belong to two different evolutionary lineages. Otiorhynchus nodosus specimens are tetraploid clones. Both species show geographical parthenogenesis, as do many other Otiorhynchus species.

    3 Mitochondrial data indicate that O. nodosus clones are more closely related to Slovenian sexuals of O. scaber than these are to sexuals from Austria. It also shows that almost all clones of O. scaber collected in one of the two regions where sexuals are found are more closely related to sexuals from the other region.

    4 Three different hypotheses that may explain the distribution of O. scaber, mechanisms important for the evolution of the clones and implications of the presence of Wolbachia are discussed.

    5 We conclude that parthenogenesis is likely to be linked to hybridization in O. scaber and that hybridization events between ancestors of O. nodosus and O. scaber are the probable cause of the presence of O. nodosus in the ingroup. We also find that polyploid clones are superior colonizers compared to sexuals and diploid clones, in O. scaber.

    6 The results suggest that systems where both sexuals and clones exist are more complex than previously suggested. The mapping of genetic variation in clonal complexes and the tracing of clonal origins may be useful in pest management.

  • 32.
    Stenberg, Per
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Science and Technology).
    Pettersson, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Saura, Anja O
    Department of Genetics, University of Helsinki, Helsinki, Finland.
    Berglund, Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Science and Technology).
    Sequence signature analysis of chromosome identity in three Drosophila species2005In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 6, no 158, p. 1-17Article in journal (Refereed)
    Abstract [en]

    Background: All eukaryotic organisms need to distinguish each of their chromosomes. A few protein complexes have been described that recognise entire, specific chromosomes, for instance dosage compensation complexes and the recently discovered autosome-specific Painting of Fourth (POF) protein in Drosophila. However, no sequences have been found that are chromosome-specific and distributed over the entire length of the respective chromosome. Here, we present a new, unbiased, exhaustive computational method that was used to probe three Drosophila genomes for chromosome-specific sequences.

    Results: By combining genome annotations and cytological data with multivariate statistics related to three Drosophila genomes we found sequence signatures that distinguish Muller's F-elements ( chromosome 4 in D. melanogaster) from all other chromosomes in Drosophila that are not attributable to differences in nucleotide composition, simple sequence repeats or repeated elements. Based on these signatures we identified complex motifs that are strongly overrepresented in the F-elements and found indications that the D. melanogaster motif may be involved in POF-binding to the F-element. In addition, the X-chromosomes of D. melanogaster and D. yakuba can be distinguished from the other chromosomes, albeit to a lesser extent. Surprisingly, the conservation of the F-element sequence signatures extends not only between species separated by approximately 55 Myr, but also linearly along the sequenced part of the F-elements.

    Conclusion: Our results suggest that chromosome-distinguishing features are not exclusive to the sex chromosomes, but are also present on at least one autosome ( the F-element) in Drosophila.

  • 33.
    Stenberg, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Saura, Anssi
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cytology of Asexual Animals2009In: Lost Sex: The Evolutionary Biology of Parthenogenesis / [ed] Isa Schön, Koen Martens, Peter Dijk, Dordrecht: Springer Netherlands, 2009, p. 63-74Chapter in book (Other academic)
    Abstract [en]

    We review the cytological mechanisms underlying asexual reproduction, i.e. reproduction without fertilization, in animals. Asexuality or parthenogenesis has evolved many times and the cytological mechanisms to restore the parental chromosome number can vary between and even within species. In automictic or meiotic parthenogenesis, meiosis takes place but the chromosomal constitution of the mother is restored through one or several different mechanisms. Some of these mechanisms enforce homozygosity at all loci while some other mechanisms pass the genome of the mother intact to the offspring. In apomictic or mitotic parthenogenesis the eggs are formed through what is essentially a set of mitoses. Polyploidy, is in general incompatible with chromosomal sex determination and is a rare condition in animals. However, many asexual and hermaphroditic forms are polyploid to various degrees. Polyploidy is divided into allo- and autopolyploidy. In the former mode the chromosome sets are derived from two or more different species while in autopolyploidy the multiplication has taken place within one species. We discuss the evolutionary consequences of the different cytological mechanisms involved in asexual reproduction.

  • 34.
    Stenberg, Per
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Saura, Anssi
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Meiosis and Its Deviations in Polyploid Animals2013In: Cytogenetic and Genome Research, ISSN 1424-8581, E-ISSN 1424-859X, Vol. 140, no 2-4, p. 185-203Article in journal (Refereed)
    Abstract [en]

    We review the different modes of meiosis and its deviations encountered in polyploid animals. Bisexual reproduction involving normal meiosis occurs in some allopolyploid frogs with variable degrees of polyploidy. Aberrant modes of bisexual reproduction include gynogenesis, where a sperm stimulates the egg to develop. The sperm may enter the egg but there is no fertilization and syngamy. In hybridogenesis, a genome is eliminated to produce haploid or diploid eggs or sperm. Ploidy can be elevated by fertilization with a haploid sperm in meiotic hybridogenesis, which elevates the ploidy of hybrid offspring such that they produce diploid gametes. Polyploids are then produced in the next generation. In kleptogenesis, females acquire full or partial genomes from their partners. In pre-equalizing hybrid meiosis, one genome is transmitted in the Mendelian fashion, while the other is transmitted clonally. Parthenogenetic animals have a very wide range of mechanisms for restoring or maintaining the mother's ploidy level, including gamete duplication, terminal fusion, central fusion, fusion of the first polar nucleus with the product of the first division, and premeiotic duplication followed by a normal meiosis. In apomictic parthenogenesis, meiosis is replaced by what is effectively mitotic cell division. The above modes have different evolutionary consequences, which are discussed. See also the sister article by Grandont et al. in this themed issue.

  • 35.
    Svensson, Malin J.
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Science and Technology).
    Stenberg, Per
    Johansson, Anna-Mia
    Larsson, Jan
    Painting of fourth in Drosophila spermatogenesisManuscript (Other academic)
  • 36.
    Svensson, Malin J
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Science and Technology).
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Science and Technology).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Science and Technology).
    Organization and regulation of sex-specific thioredoxin encoding genes in the genus Drosophila.2007In: Dev Genes Evol, ISSN 0949-944X, Vol. 217, no 9, p. 639-50Article in journal (Refereed)
    Abstract [en]

    Thioredoxins are small thiol proteins that have a

    conserved active site sequence, WCGPC, and reduce

    disulfide bonds in various proteins using the two active site

    cysteines, a reaction that oxidizes thioredoxin and renders it

    inactive. Thioredoxin reductase returns thioredoxin to its

    reduced, active form in a reaction that converts NADPH to

    NADP+. The biological functions of thioredoxins vary

    widely; they have roles in oxidative stress protection, act as

    electron donors for ribonucleotide reductase, and form

    structural components of enzymes. To date, three thioredoxin

    genes have been characterized in Drosophila melanogaster:

    the generally expressed Thioredoxin-2 (Trx-2) and the two

    sex-specific genes ThioredoxinT (TrxT) and deadhead

    (dhd). The male-specific TrxT and the female-specific dhd

    are located as a gene pair, transcribed in opposite directions,

    with only 470 bp between their transcription start points. We

    show in this study that all three D. melanogaster thioredoxins

    are conserved in 11 other Drosophilid species, which are

    believed to have diverged up to 40 Ma ago and that Trx-2 is

    conserved all the way to Tribolium castaneum. We have

    found that the intriguing gene organization and regulation of

    TrxT and dhd is remarkably well conserved and identified

    potential conserved regulatory sequences. In addition, we

    show that the 50–70 C terminal amino acids of TrxT constitute

    a hyper-variable domain, which could play a role in

    sexual conflict and male–female co-evolution.

  • 37. Yeung, Kelvin
    et al.
    Boija, Ann
    Karlsson, Edvin
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Division of CBRN Security and Defence, FOI-Swedish Defence Research Agency, Umeå, Sweden.
    Holmqvist, Per-Henrik
    Tstskis, Yonit
    Nisoli, Ilaria
    Yap, Damian
    Lorzadeh, Alireza
    Moksa, Michelle
    Hirst, Martin
    Aparicio, Samuel
    Fanto, Manolis
    Stenberg, Per
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Division of CBRN Security and Defence, FOI-Swedish Defence Research Agency, Umeå, Sweden.
    Mannervik, Mattias
    McNeill, Helen
    Atrophin controls developmental signaling pathways via interactions with Trithorax-like2017In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e23084Article in journal (Refereed)
    Abstract [en]

    Mutations in human Atrophin1, a transcriptional corepressor, cause dentatorubral-pallidoluysian atrophy, a neurodegenerative disease. Drosophila Atrophin (Atro) mutants display many phenotypes, including neurodegeneration, segmentation, patterning and planar polarity defects. Despite Atros critical role in development and disease, relatively little is known about Atros binding partners and downstream targets. We present the first genomic analysis of Atro using ChIP-seq against endogenous Atro. ChIP-seq identified 1300 potential direct targets of Atro including engrailed, and components of the Dpp and Notch signaling pathways. We show that Atro regulates Dpp and Notch signaling in larval imaginal discs, at least partially via regulation of thickveins and fringe. In addition, bioinformatics analyses, sequential ChIP and coimmunoprecipitation experiments reveal that Atro interacts with the Drosophila GAGA Factor, Trithorax-like (Trl), and they bind to the same loci simultaneously. Phenotypic analyses of Trl and Atro clones suggest that Atro is required to modulate the transcription activation by Trl in larval imaginal discs. Taken together, these data indicate that Atro is a major Trl cofactor that functions to moderate developmental gene transcription.

  • 38.
    Zare, Aman
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Johansson, Anna-Mia
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Karlsson, Edvin
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Division of CBRN Security and Defence, FOI-Swedish, Defence Research Agency, Umeå, Sweden.
    Delhomme, Nicolas
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Division of CBRN Security and Defence, FOI-Swedish, Defence Research Agency, Umeå, Sweden.
    The gut microbiome participates in transgenerational inheritance of low temperature responses in Drosophila melanogaster2018In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 592, no 24, p. 4078-4086Article in journal (Refereed)
    Abstract [en]

    Environmental perturbations induce transcriptional changes, some of which may be inherited even in the absence of the initial stimulus. Previous studies have focused on transfers through the germ-line although microbiota is also passed on to the offspring. Thus, we inspected the involvement of the gut microbiome in transgenerational inheritance of environmental exposures in Drosophila melanogaster. We grew flies in the cold versus control temperatures and compared their transcriptional patterns in both conditions as well as in their offspring. F2 flies grew in control temperature while we controlled their microbiota acquisition from either F1 sets. Transcriptional status of some genes was conserved transgenerationally, and a subset of these genes, mainly expressed in the gut, was transcriptionally dependent on the acquired microbiome. This article is protected by copyright. All rights reserved.

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