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Some microsatellites may act as novel polymorphic cis-regulatory elements through transcription factor binding
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
2004 In: Gene, ISSN 0378-1119, Vol. 341, 149-165 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2004. Vol. 341, 149-165 p.
URN: urn:nbn:se:uu:diva-95425OAI: oai:DiVA.org:uu-95425DiVA: diva2:169623
Available from: 2007-02-08 Created: 2007-02-08Bibliographically approved
In thesis
1. From Single Gene to Whole Genome Studies of Human Transcription Regulation
Open this publication in new window or tab >>From Single Gene to Whole Genome Studies of Human Transcription Regulation
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Transcriptional regulation largely determines which proteins and the protein levels that are found in a cell, and this is crucial in development, differentiation and responses to environmental stimuli. The major effectors of transcriptional regulation are a group of proteins known as transcription factors, which importance is supported by their frequent involvement in mendelian and complex diseases.

In paper I, we attempted to establish the importance of DNA sequence variation in transcriptional control, by analyzing the potential functionality of polymorphic short repetitive elements as cis-regulatory elements. However, the relevance of this study was constrained by the limited number of analyzed sequences and the in vitro nature of the experiments. To overcome these limitations, (paper II) we optimized an in vivo large-scale technology named ChIP-chip, which couples chromatin immunoprecipitation and microarray hybridization. We successfully identified the binding profiles of metabolic-disease associated transcription factors in 1% of the human genome, using a liver cellular model, and inferred the binding sites at base pair resolution.

Another important characteristic of transcriptional regulation is its plasticity, which allows adjusting the cellular transcriptome to cellular and environmental stimuli. In paper III, we investigated such plasticity by treating HepG2 cells with butyrate, a histone deacetylase inhibitor (HDACi) and interrogating the changes in histone H3 and H4 acetylation levels in 1% of the genome. Observation of frequent deacetylation around transcription start sites and hyperacetylation at the nuclear periphery challenges pre-assumed HDACi mechanisms of action.

Finally, in paper IV we extended the DNA binding profiles of the medically relevant transcription factors, USF1 and USF2, and H3 acetylation to the whole non-repetitive fraction of the human genome. Using motif finding tools and chromatin profiling, we uncovered the major determinants of USF-DNA interactions. Furthermore, USFs and H3ac were clearly localized around transcription start sites, frequently in the context of bidirectional promoters.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 52 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 222
Genetics, transcription, ChIP-chip, genome-wide, transcription factors, in vivo, Genetik
urn:nbn:se:uu:diva-7463 (URN)978-91-554-6790-3 (ISBN)
Public defence
2007-03-02, Rudbeck Hall, Rudbeck Laboratory, Dag Hammarsjöld, 20, Uppsala, 13:15
Available from: 2007-02-08 Created: 2007-02-08 Last updated: 2013-09-20Bibliographically approved

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