Publications
Download:
File size:
2729 kb
Format:
application/pdf
Author:
Andersson, Robin (Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics)
Title:
Decoding the Structural Layer of Transcriptional Regulation: Computational Analyses of Chromatin and Chromosomal Aberrations
Department:
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics
Publication type:
Doctoral thesis, comprehensive summary (Other academic)
Language:
English
Place of publ.: Uppsala Publisher: Acta Universitatis Upsaliensis
Pages:
76
Series:
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214; 768
Year of publ.:
2010
URI:
urn:nbn:se:uu:diva-130999
Permanent link:
http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-130999
ISBN:
978-91-554-7897-1
Subject category:
Bioinformatics and Systems Biology
SVEP category:
Bioinformatics
Research subject:
Bioinformatics
Keywords(en) :
Chromatin, Nucleosome positioning, Histone modifications, Chromosomal aberrations, Transcriptional regulation, Array-CGH, Next generation sequencing, ChIP-chip
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.

Public defence:
2010-11-02, C4:305, BMC, Husargatan 3, Uppsala, 09:00 (English)
Degree:
degree of Doctor of Philosophy
Supervisor:
Komorowski, Jan, Professor (Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics)
Dumanski, Jan, Professor (Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology)
Wadelius, Claes, Professor (Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology)
Opponent:
Krogh, Anders, Professor (University of Copenhagen, Department of Molecuar Biology)
Available from:
2010-10-12
Created:
2010-09-20
Last updated:
2010-11-11
Statistics:
322 hits
FILE INFORMATION
File size:
2729 kb
Mimetype:
application/pdf
Type:
fulltext
Statistics:
761 hits