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Nucleosomes are well positioned in exons and carry characteristic histone modifications
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2009 (English)In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 19, no 10, 1732-1741 p.Article in journal (Refereed) Published
Abstract [en]

The genomes of higher organisms are packaged in nucleosomes with functional histone modifications. Until now, genome-wide nucleosome and histone modification studies have focused on transcription start sites (TSSs) where nucleosomes in RNA polymerase II (RNAPII) occupied genes are well positioned and have histone modifications that are characteristic of expression status. Using public data, we here show that there is a higher nucleosome-positioning signal in internal human exons and that this positioning is independent of expression. We observed a similarly strong nucleosome-positioning signal in internal exons of C. elegans. Among the 38 histone modifications analyzed in man, H3K36me3, H3K79me1, H2BK5me1, H3K27me1, H3K27me2 and H3K27me3 had evidently higher signal in internal exons than in the following introns and were clearly related to exon expression. These observations are suggestive of roles in splicing. Thus, exons are not only characterized by their coding capacity but also by their nucleosome organization, which seems evolutionary conserved since it is present in both primates and nematodes.

Place, publisher, year, edition, pages
2009. Vol. 19, no 10, 1732-1741 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-107609DOI: 10.1101/gr.092353.109ISI: 000270389700005PubMedID: 19687145OAI: oai:DiVA.org:uu-107609DiVA: diva2:232088
Note

De tre första författarna delar första författarskapet.

Available from: 2009-08-19 Created: 2009-08-19 Last updated: 2017-02-02Bibliographically approved
In thesis
1. Decoding the Structural Layer of Transcriptional Regulation: Computational Analyses of Chromatin and Chromosomal Aberrations
Open this publication in new window or tab >>Decoding the Structural Layer of Transcriptional Regulation: Computational Analyses of Chromatin and Chromosomal Aberrations
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Gene activity is regulated at two separate layers. Through structural and chemical properties of DNA – the primary layer of encoding – local signatures may enable, or disable, the binding of proteins or complexes of them with regulatory potential to the DNA. At a higher level – the structural layer of encoding – gene activity is regulated through the properties of higher order DNA structure, chromatin, and chromosome organization. Cells with abnormal chromosome compaction or organization, e.g. cancer cells, may thus have perturbed regulatory activities resulting in abnormal gene activity.

Hence, there is a great need to decode the transcriptional regulation encoded in both layers to further our understanding of the factors that control activity and life of a cell and, ultimately, an organism. Modern genome-wide studies with those aims rely on data-intense experiments requiring sophisticated computational and statistical methods for data handling and analyses. This thesis describes recent advances of analyzing experimental data from quantitative biological studies to decipher the structural layer of encoding in human cells.

Adopting an integrative approach when possible, combining multiple sources of data, allowed us to study the influences of chromatin (Papers I and II) and chromosomal aberrations (Paper IV) on transcription. Combining chromatin data with chromosomal aberration data allowed us to identify putative driver oncogenes and tumor-suppressor genes in cancer (Paper IV).

Bayesian approaches enabling the incorporation of background information in the models and the adaptability of such models to data have been very useful. Their usages yielded accurate and narrow detection of chromosomal breakpoints in cancer (Papers III and IV) and reliable positioning of nucleosomes and their dynamics during transcriptional regulation at functionally relevant regulatory elements (Paper II).

Using massively parallel sequencing data, we explored the chromatin landscapes of human cells (Papers I and II) and concluded that there is a preferential and evolutionary conserved positioning at internal exons nearly unaffected by the transcriptional level. We also observed a strong association between certain histone modifications and the inclusion or exclusion of an exon in the mature gene transcript, suggesting a functional role in splicing.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 768
Keyword
Chromatin, Nucleosome positioning, Histone modifications, Chromosomal aberrations, Transcriptional regulation, Array-CGH, Next generation sequencing, ChIP-chip
National Category
Bioinformatics and Systems Biology
Research subject
Bioinformatics
Identifiers
urn:nbn:se:uu:diva-130999 (URN)978-91-554-7897-1 (ISBN)
Public defence
2010-11-02, C4:305, BMC, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2010-10-12 Created: 2010-09-20 Last updated: 2010-11-11Bibliographically approved

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Enroth, StefanWadelius, ClaesKomorowski, Jan

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