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Whole-genome maps of USF1 and USF2 binding and histone H3 acetylation reveal new aspects of promoter structure and candidate genes for common human disorders
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
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2008 (English)In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 18, no 3, 380-392 p.Article in journal (Refereed) Published
Abstract [en]

Transcription factors and histone modifications are crucial regulators of gene expression that mutually influence each other. We present the DNA binding profiles of upstream stimulatory factors 1 and 2 (USF1, USF2) and acetylated histone H3 (H3ac) in a liver cell line for the whole human genome using ChIP-chip at a resolution of 35 base pairs. We determined that these three proteins bind mostly in proximity of protein coding genes transcription start sites (TSSs), and their bindings are positively correlated with gene expression levels. Based on the spatial and functional relationship between USFs and H3ac at protein coding gene promoters, we found similar promoter architecture for known genes and the novel and less-characterized transcripts human mRNAs and spliced ESTs. Furthermore, our analysis revealed a previously underestimated abundance of genes in a bidirectional conformation, where USFs are bound in between TSSs. After taking into account this promoter conformation, the results indicate that H3ac is mainly located downstream of TSS, and it is at this genomic location where it positively correlates with gene expression. Finally, USF1, which is associated to familial combined hyperlipidemia, was found to bind and potentially regulate nuclear mitochondrial genes as well as genes for lipid and cholesterol metabolism, frequently in collaboration with GA binding protein transcription factor alpha (GABPA, nuclear respiratory factor 2 [NRF-2]). This expands our understanding about the transcriptional control of metabolic processes and its alteration in metabolic disorders.

Place, publisher, year, edition, pages
2008. Vol. 18, no 3, 380-392 p.
National Category
Bioinformatics and Systems Biology
Identifiers
URN: urn:nbn:se:uu:diva-97706DOI: 10.1101/gr.6880908ISI: 000253766700004PubMedID: 18230803OAI: oai:DiVA.org:uu-97706DiVA: diva2:172747
Available from: 2008-11-06 Created: 2008-11-06 Last updated: 2017-02-02Bibliographically approved
In thesis
1. A Bioinformatics Study of Human Transcriptional Regulation
Open this publication in new window or tab >>A Bioinformatics Study of Human Transcriptional Regulation
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Regulation of transcription is a central mechanism in all living cells that now can be investigated with high-throughput technologies. Data produced from such experiments give new insights to how transcription factors (TFs) coordinate the gene transcription and thereby regulate the amounts of proteins produced. These studies are also important from a medical perspective since TF proteins are often involved in disease. To learn more about transcriptional regulation, we have developed strategies for analysis of data from microarray and massively parallel sequencing (MPS) experiments.

Our computational results consist of methods to handle the steadily increasing amount of data from high-throughput technologies. Microarray data analysis tools have been assembled in the LCB-Data Warehouse (LCB-DWH) (paper I), and other analysis strategies have been developed for MPS data (paper V). We have also developed a de novo motif search algorithm called BCRANK (paper IV).

The analysis has lead to interesting biological findings in human liver cells (papers II-V). The investigated TFs appeared to bind at several thousand sites in the genome, that we have identified at base pair resolution. The investigated histone modifications are mainly found downstream of transcription start sites, and correlated to transcriptional activity. These histone marks are frequently found for pairs of genes in a bidirectional conformation. Our results suggest that a TF can bind in the shared promoter of two genes and regulate both of them.

From a medical perspective, the genes bound by the investigated TFs are candidates to be involved in metabolic disorders. Moreover, we have developed a new strategy to detect single nucleotide polymorphisms (SNPs) that disrupt the binding of a TF (paper IV). We further demonstrated that SNPs can affect transcription in the immediate vicinity. Ultimately, our method may prove helpful to find disease-causing regulatory SNPs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 52 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 566
Keyword
bioinformatics, microarray, ChIP-chip, ChIP-seq, transcription factor, histone modification, motif search
National Category
Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:uu:diva-9346 (URN)978-91-554-7324-2 (ISBN)
Public defence
2008-11-28, C8:305, BMC, Husargatan 3, Uppsala, 09:00
Opponent
Supervisors
Available from: 2008-11-06 Created: 2008-11-06 Last updated: 2013-09-20Bibliographically approved
2. 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 222
Keyword
Genetics, transcription, ChIP-chip, genome-wide, transcription factors, in vivo, Genetik
Identifiers
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
Opponent
Supervisors
Available from: 2007-02-08 Created: 2007-02-08 Last updated: 2013-09-20Bibliographically approved

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Enroth, StefanWadelius, Claes

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