Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology. (Helena Jernberg Wiklund)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux 2, rue , Robert Escarpit, 33607 Pessac, France..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
Show others and affiliations
2016 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 15, no 12, 1558-1571 p.Article in journal (Refereed) Published
Abstract [en]

CGGBP1 (CGG triplet repeat-binding protein 1) regulates cell proliferation, stress response,cytokinesis, telomeric integrity and transcription. It could affect these processes by modulatingtarget gene expression under different conditions. Identification of CGGBP1-target genes andtheir regulation could reveal how a transcription regulator affects such diverse cellular processes.Here we describe the mechanisms of differential gene expression regulation by CGGBP1 inquiescent or growing cells. By studying global gene expression patterns and genome-wide DNAbindingpatterns of CGGBP1, we show that a possible mechanism through which it affects theexpression of RNA Pol II-transcribed genes in trans depends on Alu RNA. We also show that itregulates Alu transcription in cis by binding to Alu promoter. Our results also indicate thatpotential phosphorylation of CGGBP1 upon growth stimulation facilitates its nuclear retention,Alu-binding and dislodging of RNA Pol III therefrom. These findings provide insights into howAlu transcription is regulated in response to growth signals.

Place, publisher, year, edition, pages
2016. Vol. 15, no 12, 1558-1571 p.
Keyword [en]
Alu-SINEs; CGGBP1; ChIP-seq; growth signals; RNA Pol III; transcription; tyrosine phosphorylation
National Category
Cell Biology
Research subject
Bioinformatics; Biology
Identifiers
URN: urn:nbn:se:uu:diva-230959DOI: 10.4161/15384101.2014.967094ISI: 000379743800011PubMedID: 25483050OAI: oai:DiVA.org:uu-230959DiVA: diva2:742480
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2014-09-01 Created: 2014-09-01 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Regulation of Gene Expression in Multiple Myeloma Cells and Normal Fibroblasts: Integrative Bioinformatic and Experimental Approaches
Open this publication in new window or tab >>Regulation of Gene Expression in Multiple Myeloma Cells and Normal Fibroblasts: Integrative Bioinformatic and Experimental Approaches
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The work presented in this thesis applies integrative genomic and experimental approaches to investigate mechanisms involved in regulation of gene expression in the context of disease and normal cell biology.

In papers I and II, we have explored the role of epigenetic regulation of gene expression in multiple myeloma (MM). By using a bioinformatic approach we identified the Polycomb repressive complex 2 (PRC2) to be a common denominator for the underexpressed gene signature in MM. By using inhibitors of the PRC2 we showed an activation of the genes silenced by H3K27me3 and a reduction in the tumor load and increased overall survival in the in vivo 5TMM model. Using ChIP-sequencing we defined the distribution of H3K27me3 and H3K4me3 marks in MM patients cells. In an integrated bioinformatic approach, the H3K27me3-associated genes significantly correlated to under-expression in patients with less favorable survival. Thus, our data indicates the presence of a common under-expressed gene profile and provides a rationale for implementing new therapies focusing on epigenetic alterations in MM.

In paper III we address the existence of a small cell population in MM presenting with differential tumorigenic properties in the 5T33MM murine model. We report that the predominant population of CD138+ cells had higher engraftment potential, higher clonogenic growth, whereas the CD138- MM cells presented with less mature phenotype and higher drug resistance. Our findings suggest that while designing treatment regimes for MM, both the cellpopulations must be targeted.

In paper IV we have studied the general mechanism of differential gene expression regulation by CGGBP1 in response to growth signals in normal human fibroblasts. We found that CGGBP1 binding affects global gene expression by RNA Polymerase II. This is mediated by Alu RNAdependentinhibition of RNA Polymerase II. In presence of growth signals CGGBP1 is retained in the nuclei and exhibits enhanced Alu binding thus inhibiting RNA Polymerase III binding on Alus. Hence we suggest a mechanism by which CGGBP1 orchestrates Alu RNA-mediated regulation of RNA Polymerase II. This thesis provides new insights for using integrative bioinformatic approaches to decipher gene expression regulation mechanisms in MM and in normal cells.

Place, publisher, year, edition, pages
uppsala: Acta Universitatis Upsaliensis, 2014. 71 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1029
Keyword
Multiple myeloma, Integrative bioinformatics, Epigenetics, CGGBP1, RNA polymerase
National Category
Cell and Molecular Biology Genetics Bioinformatics (Computational Biology)
Research subject
Oncology; Bioinformatics
Identifiers
urn:nbn:se:uu:diva-232949 (URN)978-91-554-9045-4 (ISBN)
Public defence
2014-11-13, Rudbecksalen, Dag Hammarskjolds vag 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-10-22 Created: 2014-10-22 Last updated: 2015-02-04Bibliographically approved

Open Access in DiVA

fulltext(1695 kB)157 downloads
File information
File name FULLTEXT02.pdfFile size 1695 kBChecksum SHA-512
a08cc5728ee912c466d30594cdaa559bbfa890b236f59315465f101051e7b2510bc5897b365d42aa00fe9cb4571244549f0c0e375ee2603573d1f1dcc74bf8e7
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Agarwal, PrasoonEnroth, StefanJernberg Wiklund, HelenaWestermark, BengtSingh, Umashankar
By organisation
Hematology and ImmunologyGenomicsCancer and Vascular Biology
In the same journal
Cell Cycle
Cell Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 157 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 922 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf