Genome-Wide Studies of Transcriptional Regulation in Human Liver Cells by High-throughput Sequencing
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 904
ChIP-seq, Transcription factors, Alcoholic steatohepatitis, Genome-wide, GWAS, SNPs
IdentifiersURN: urn:nbn:se:uu:diva-198579ISBN: 978-91-554-8671-6OAI: oai:DiVA.org:uu-198579DiVA: diva2:617444
2013-06-10, Rudbeck hall, The Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Mannervik, Mattias, Professor
Wadelius, Claes, Professor
List of papers