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Genome-Wide Studies of Transcriptional Regulation in Human Liver Cells by High-throughput Sequencing
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The human genome contains slightly more than 20 000 genes that are expressed in a tissue specific manner. Transcription factors play a key role in gene regulation. By mapping the transcription factor binding sites genome-wide we can understand their role in different biological processes. In this thesis we have mapped transcription factors and histone marks along with nucleosome positions and RNA levels. In papers I and II, we used ChIP-seq to map five liver specific transcription factors that are crucial for liver development and function. We showed that the mapped transcription factors are involved in metabolism and other cellular processes. We showed that ChIP-seq can also be used to detect protein-protein interactions and functional SNPs. Finally, we showed that the epigenetic histone mark studied in paper I is associated with transcriptional activity at promoters. In paper III, we mapped nucleosome positions before and after treatment with transforming growth factor  β (TGFβ) and found that many nucleosomes changed positions when expression changed. After treatment with TGFβ, the transcription factor HNF4α was replaced by a nucleosome in some regions. In paper IV, we mapped USF1 transcription factor and three active chromatin marks in normal liver tissue and in liver tissue of patients diagnosed with alcoholic steatohepatitis. Using gene ontology, we as expected identified many metabolism related genes as active in normal samples whereas genes in cancer pathways were active in steatohepatitis tissue. Cancer is a common complication to the disease and early signs of this were found. We also found many novel and GWAS catalogue SNPs that are candidates to be functional. In conclusion, our results have provided information on location and structure of regulatory elements which will lead to better knowledge on liver function and disease.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 50 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 904
Keyword [en]
ChIP-seq, Transcription factors, Alcoholic steatohepatitis, Genome-wide, GWAS, SNPs
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-198579ISBN: 978-91-554-8671-6 (print)OAI: oai:DiVA.org:uu-198579DiVA: diva2:617444
Public defence
2013-06-10, Rudbeck hall, The Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2013-05-20 Created: 2013-04-21 Last updated: 2013-08-30Bibliographically approved
List of papers
1. Differential binding and co-binding pattern of FOXA1 and FOXA3 and their relation to H3K4me3 in HepG2 cells revealed by ChIP-seq
Open this publication in new window or tab >>Differential binding and co-binding pattern of FOXA1 and FOXA3 and their relation to H3K4me3 in HepG2 cells revealed by ChIP-seq
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2009 (English)In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 10, no 11, R129- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The forkhead box/winged helix family members FOXA1, FOXA2, and FOXA3 are of high importance in development and specification of the hepatic linage and the continued expression of liver-specific genes. RESULTS: Here, we present a genome-wide location analysis of FOXA1 and FOXA3 binding sites in HepG2 cells through chromatin immunoprecipitation with detection by sequencing (ChIP-seq) studies and compare these with our previous results on FOXA2. We found that these factors often bind close to each other in different combinations and consecutive immunoprecipitation of chromatin for one and then a second factor (ChIP-reChIP) shows that this occurs in the same cell and on the same DNA molecule, suggestive of molecular interactions. Using co-immunoprecipitation, we further show that FOXA2 interacts with both FOXA1 and FOXA3 in vivo, while FOXA1 and FOXA3 do not appear to interact. Additionally, we detected diverse patterns of trimethylation of lysine 4 on histone H3 (H3K4me3) at transcriptional start sites and directionality of this modification at FOXA binding sites. Using the sequence reads at polymorphic positions, we were able to predict allele specific binding for FOXA1, FOXA3, and H3K4me3. Finally, several SNPs associated with diseases and quantitative traits were located in the enriched regions. CONCLUSIONS: We find that ChIP-seq can be used not only to create gene regulatory maps but also to predict molecular interactions and to inform on the mechanisms for common quantitative variation.

National Category
Medical and Health Sciences Biological Sciences
Identifiers
urn:nbn:se:uu:diva-119751 (URN)10.1186/gb-2009-10-11-r129 (DOI)000273344600016 ()19919681 (PubMedID)
Note

De två (2) första författarna delar förstaförfattarskapet.

Available from: 2010-03-01 Created: 2010-03-01 Last updated: 2017-12-12Bibliographically approved
2. Molecular interactions between HNF4a, FOXA2 and GABP identified at regulatory DNA elements through ChIP-sequencing
Open this publication in new window or tab >>Molecular interactions between HNF4a, FOXA2 and GABP identified at regulatory DNA elements through ChIP-sequencing
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2009 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 37, no 22, 7498-7508 p.Article in journal (Refereed) Published
Abstract [en]

Gene expression is regulated by combinations of transcription factors, which can be mapped to regulatory elements on a genome-wide scale using ChIP experiments. In a previous ChIP-chip study of USF1 and USF2 we found evidence also of binding of GABP, FOXA2 and HNF4a within the enriched regions. Here, we have applied ChIP-seq for these transcription factors and identified 3064 peaks of enrichment for GABP, 7266 for FOXA2 and 18783 for HNF4a. Distal elements with USF2 signal was frequently bound also by HNF4a and FOXA2. GABP peaks were found at transcription start sites, whereas 94% of FOXA2 and 90% of HNF4a peaks were located at other positions. We developed a method to accurately define TFBS within peaks, and found the predicted sites to have an elevated conservation level compared to peak centers; however the majority of bindings were not evolutionary conserved. An interaction between HNF4a and GABP was seen at TSS, with one-third of the HNF4a positive promoters being bound also by GABP, and this interaction was verified by co-immunoprecipitations.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-121011 (URN)10.1093/nar/gkp823 (DOI)000272935000022 ()19822575 (PubMedID)
Available from: 2010-03-18 Created: 2010-03-18 Last updated: 2017-12-12Bibliographically approved
3. Nucleosome regulatory dynamics in response to TGF-beta treatment in HepG2 cells
Open this publication in new window or tab >>Nucleosome regulatory dynamics in response to TGF-beta treatment in HepG2 cells
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2014 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 42, no 11, 6921-6934 p.Article in journal (Refereed) Published
National Category
Medical Genetics
Research subject
Molecular Genetics; Medical Genetics
Identifiers
urn:nbn:se:uu:diva-198545 (URN)10.1093/nar/gku326 (DOI)
Available from: 2013-04-21 Created: 2013-04-19 Last updated: 2017-12-06
4. ChIP-seq in steatohepatitis and normal liver tissue identifies candidate disease mechanisms related to progression to cancer
Open this publication in new window or tab >>ChIP-seq in steatohepatitis and normal liver tissue identifies candidate disease mechanisms related to progression to cancer
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(English)Manuscript (preprint) (Other academic)
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-198552 (URN)
Available from: 2013-04-21 Created: 2013-04-19 Last updated: 2013-05-14Bibliographically approved

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