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Sequence signatures involved in targeting the male-specific lethal complex to X-chromosomal genes in Drosophila melanogaster
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). (Per Stenberg)ORCID-id: 0000-0001-8752-0794
Umbio, 907 19 Umeå, Sweden.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). (Computational Life Science Cluster (CLiC))
2012 (Engelska)Ingår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, s. 97-Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
BioMed Central, 2012. Vol. 13, s. 97-
Nyckelord [en]
Dosage compensation, sequence signatures, drosophila, motif discovery, MSL-complex
Nationell ämneskategori
Bioinformatik och systembiologi Genetik
Forskningsämne
genetik
Identifikatorer
URN: urn:nbn:se:umu:diva-53363DOI: 10.1186/1471-2164-13-97ISI: 000304155400002PubMedID: 22424303OAI: oai:DiVA.org:umu-53363DiVA, id: diva2:511740
Tillgänglig från: 2012-03-23 Skapad: 2012-03-23 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. Mining DNA elements involved in targeting of chromatin modifiers
Öppna denna publikation i ny flik eller fönster >>Mining DNA elements involved in targeting of chromatin modifiers
2014 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Background: In all higher organisms, the nuclear DNA is condensed into nucleosomes that consist of DNA wrapped around a core of highly conserved histone proteins. DNA bound to histones and other structural proteins form the chromatin. Generally, only few regions of DNA are accessible and most of the time RNA polymerase and other DNA binding proteins have to overcome this compaction to initiate transcription. Several proteins are involved in making the chromatin more compact or open. Such chromatin-modifying proteins make distinct post-translational modifications of histones – especially in the histone tails – to alter their affinity to DNA. Aim: The main aim of my thesis work is to study the targeting of chromatin modifiers important for correct gene expression in Drosophila melanogaster (fruit flies). Primary DNA sequences, chromatin associated proteins, transcription, and non-coding RNAs are all likely to be involved in targeting mechanisms. This thesis work involves the development of new computational methods for identification of DNA motifs and protein factors involved in the targeting of chromatin modifiers. Targeting and functional analysis of two chromatin modifiers, namely male-specific lethal (MSL) complex and CREB-binding protein (CBP) are specifically studied. The MSL complex is a protein complex that mediates dosage compensation in flies. CBP protein is known as a transcriptional co-regulator in metazoans and it has histone acetyl transferase activity and CBP has been used to predict novel enhancers. Results: My studies of the binding sites of MSL complex shows that promoters and coding sequences of MSL-bound genes on the X-chromosome of Drosophila melanogaster can influence the spreading of the complex along the X-chromosome. Analysis of MSL binding sites when two non-coding roX RNAs are mutated shows that MSL-complex recruitment to high-affinity sites on the Xchromosome is independent of roX, and the role of roX RNAs is to prevent binding to repeats in autosomal sites. Functional analysis of MSL-bound genes using their dosage compensation status shows that the function of the MSL complex is to enhance the expression of short housekeeping genes, but MSL-independent mechanisms exist to achieve complete dosage compensation. Studies of the binding sites of the CBP protein show that, in early embryos, Dorsal in cooperation with GAGA factor (GAF) and factors like Medea and Dichaete target CBP to its binding sites. In the S2 cell line, GAF is identified as the targeting factor of CBP at promoters and enhancers, and GAF and CBP together are found to induce high levels of polymerase II pausing at promoters. In another study using integrated data analysis, CBP binding sites could be classified into polycomb protein binding sites, repressed enhancers, insulator protein-bound regions, active promoters, and active enhancers, and this suggested different potential roles for CBP. A new approach was also developed to eliminate technical bias in skewed experiments. Our study shows that in the case of skewed datasets it is always better to identify non-altered variables and to normalize the data using only such variables.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2014. s. 76
Nyckelord
nucleosome, histone, chromatin, chromatin modifiers, targeting, DNA motifs, protein factors, MSL
Nationell ämneskategori
Bioinformatik och systembiologi Biokemi och molekylärbiologi Genetik
Forskningsämne
molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-92979 (URN)978-91-7601-118-8 (ISBN)
Disputation
2014-10-03, E 04 Unod R1, Norrland University Hospital, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2014-09-12 Skapad: 2014-09-09 Senast uppdaterad: 2018-06-07Bibliografiskt granskad

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