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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, 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 [en]
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)oai:DiVA.org:uu-130999 (OAI)diva2:352369 (DiVA)
Public defence
2010-11-02, C4:305, BMC, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from2010-10-12 Created:2010-09-20 Last updated:2010-11-11Bibliographically approved
List of papers
1. Nucleosomes are well positioned in exons and carry characteristic histone modifications
Open this publication in new window or tab >>Nucleosomes are well positioned in exons and carry characteristic histone modifications
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2009 (English)In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 19, no 10, 1732-1741Article 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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-107609 (URN)10.1101/gr.092353.109 (DOI)000270389700005 ()19687145 (PubMedID)
Note
<p><strong>De tre första författarna delar första författarskapet.</strong></p>Available from2009-08-19 Created:2009-08-19 Last updated:2013-08-29Bibliographically approved
2. Strand-based mixture modeling of nucleosome positioning in HepG2 cells and their regulatory dynamics in response to TGF-beta treatment
Open this publication in new window or tab >>Strand-based mixture modeling of nucleosome positioning in HepG2 cells and their regulatory dynamics in response to TGF-beta treatment
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(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:uu:diva-130998 (URN)
Available from2010-09-20 Created:2010-09-20 Last updated:2010-11-11
3. A Segmental Maximum A Posteriori Approach to Genome-wide Copy Number Profiling
Open this publication in new window or tab >>A Segmental Maximum A Posteriori Approach to Genome-wide Copy Number Profiling
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2008 (English)In: Bioinformatics, ISSN 1367-4803, Vol. 24, no 6, 751-758Article in journal (Other academic) Published
Abstract [en]

MOTIVATION: Copy number profiling methods aim at assigning DNA copy numbers to chromosomal regions using measurements from microarray-based comparative genomic hybridizations. Among the proposed methods to this end, Hidden Markov Model (HMM)-based approaches seem promising since DNA copy number transitions are naturally captured in the model. Current discrete-index HMM-based approaches do not, however, take into account heterogeneous information regarding the genomic overlap between clones. Moreover, the majority of existing methods are restricted to chromosome-wise analysis. RESULTS: We introduce a novel Segmental Maximum A Posteriori approach, SMAP, for DNA copy number profiling. Our method is based on discrete-index Hidden Markov Modeling and incorporates genomic distance and overlap between clones. We exploit a priori information through user-controllable parameterization that enables the identification of copy number deviations of various lengths and amplitudes. The model parameters may be inferred at a genome-wide scale to avoid overfitting of model parameters often resulting from chromosome-wise model inference. We report superior performances of SMAP on synthetic data when compared with two recent methods. When applied on our new experimental data, SMAP readily recognizes already known genetic aberrations including both large-scale regions with aberrant DNA copy number and changes affecting only single features on the array. We highlight the differences between the prediction of SMAP and the compared methods and show that SMAP accurately determines copy number changes and benefits from overlap consideration.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-13616 (URN)10.1093/bioinformatics/btn003 (DOI)000254010400003 ()18204059 (PubMedID)
Available from2008-08-21 Created:2008-08-21 Last updated:2010-11-11Bibliographically approved
4. Integrative epigenomic and genomic analysis of malignant pheochromocytoma
Open this publication in new window or tab >>Integrative epigenomic and genomic analysis of malignant pheochromocytoma
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2010 (English)In: Experimental and Molecular Medicine, ISSN 1226-3613, Vol. 42, no 7, 484-502Article in journal (Refereed) Published
Abstract [en]

Epigenomic and genomic changes affect gene expression and contribute to tumor development. The histone modifications trimethylated histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3) are epigenetic regulators associated to active and silenced genes, respectively and alterations of these modifications have been observed in cancer. Furthermore, genomic aberrations such as DNA copy number changes are common events in tumors. Pheochromocytoma is a rare endocrine tumor of the adrenal gland that mostly occurs sporadic with unknown epigenetic/genetic cause. The majority of cases are benign. Here we aimed to combine the genome-wide profiling of H3K4me3 and H3K27me3, obtained by the ChIP-chip methodology, and DNA copy number data with global gene expression examination in a malignant pheochromocytoma sample. The integrated analysis of the tumor expression levels, in relation to normal adrenal medulla, indicated that either histone modifications or chromosomal alterations, or both, have great impact on the expression of a substantial fraction of the genes in the investigated sample. Candidate tumor suppressor genes identified with decreased expression, a H3K27me3 mark and/or in regions of deletion were for instance TGIF1, DSC3, TNFRSF10B, RASSF2, HOXA9, PTPRE and CDH11. More genes were found with increased expression, a H3K4me3 mark, and/or in regions of gain. Potential oncogenes detected among those were GNAS, INSM1, DOK5, ETV1, RET, NTRK1, IGF2, and the H3K27 trimethylase gene EZH2. Our approach to associate histone methylations and DNA copy number changes to gene expression revealed apparent impact on global gene transcription, and enabled the identification of candidate tumor genes for further exploration.

Keyword
histone code, DNA copy number changes, gene expression, oncogenes, pheochromocytoma, tumor suppressor genes
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-129532 (URN)10.3858/emm.2010.42.7.050 (DOI)000280558100002 ()20534969 (PubMedID)
Available from2010-08-18 Created:2010-08-18 Last updated:2013-08-29Bibliographically approved

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