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A high resolution genome-wide scan of HNF4? recognition sites infers a regulatory gene network in colon cancer.

ABSTRACT: The hepatic nuclear factor HNF4? is a versatile transcription factor and controls expression of many genes in development, metabolism and disease. To delineate its regulatory gene network in colon cancer and to define novel gene targets a comprehensive genome-wide scan was carried out at a resolution of 35 bp with chromatin IP DNA obtained from the human colon carcinoma cell line Caco-2 that is a particularly rich source of HNF4?. More than 90% of HNF4? binding sites were mapped as promoter distal sequences while enhancer elements could be defined to foster chromatin loops for interaction with other promoter-bound transcription factors. Sequence motif analysis by various genetic algorithms evidenced a unique enhanceosome that consisted of the nuclear proteins ER?, AP1, GATA and HNF1? as cooperating transcription factors. Overall >17,500 DNA binding sites were identified with a gene/binding site ratio that differed >6-fold between chromosomes and clustered in distinct chromosomal regions amongst >6600 genes targeted by HNF4?. Evidence is presented for nuclear receptor cross-talk of HNF4? and estrogen receptor ? that is recapitulated at the sequence level. Remarkably, the Y-chromosome is devoid of HNF4? binding sites. The functional importance of enrichment sites was confirmed in genome-wide gene expression studies at varying HNF4? protein levels. Taken collectively, a genome-wide scan of HNF4? binding sites is reported to better understand basic mechanisms of transcriptional control of HNF4? targeted genes. Novel promoter distal binding sites are identified which form an enhanceosome thereby facilitating RNA processing events.

SUBMITTER: Weltmeier F

PROVIDER: S-EPMC3145629 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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A high resolution genome-wide scan of HNF4α recognition sites infers a regulatory gene network in colon cancer.

Weltmeier Fridtjof F Borlak Juergen J

PloS one 20110728 7

The hepatic nuclear factor HNF4α is a versatile transcription factor and controls expression of many genes in development, metabolism and disease. To delineate its regulatory gene network in colon cancer and to define novel gene targets a comprehensive genome-wide scan was carried out at a resolution of 35 bp with chromatin IP DNA obtained from the human colon carcinoma cell line Caco-2 that is a particularly rich source of HNF4α. More than 90% of HNF4α binding sites were mapped as promoter dist ...[more]

PMID: 21829439

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Project description:The unfolded protein response (UPR) responds to disruption of endoplasmic reticulum (ER) function by initiating signaling cascades that ultimately culminate in extensive transcriptional regulation. Classically, this regulation includes genes encoding ER chaperones, ER-associated degradation factors, and others involved in secretory protein folding and processing, and is carried out by the transcriptional activators that are produced as a consequence of UPR activation. However, up to half of the mRNAs regulated by ER stress are downregulated rather than upregulated, and the mechanisms linking ER stress and UPR activation to mRNA suppression are poorly understood. To begin to address this issue, we used a "bottom-up" approach to study the metabolic gene regulatory network controlled by the UPR in the liver, because ER stress in the liver leads to lipid accumulation, and fatty liver disease is the most common liver disease in the western world. qRT-PCR profiling of mouse liver mRNAs during ER stress revealed that suppression of the transcriptional regulators C/EBP?, PPAR?, and PGC-1? preceded lipid accumulation, and was then followed by suppression of mRNAs encoding key enzymes involved in fatty acid oxidation and lipoprotein biogenesis and transport. Mice lacking the ER stress sensor ATF6?, which experience persistent ER stress and profound lipid accumulation during challenge, were then used as the basis for a functional genomics approach that allowed genes to be grouped into distinct expression profiles. This clustering predicted that ER stress would suppress the activity of the metabolic transcriptional regulator HNF4?-a finding subsequently confirmed by chromatin immunopreciptation at the Cebpa and Pgc1a promoters. Our results establish a framework for hepatic gene regulation during ER stress and suggest that HNF4? occupies the apex of that framework. They also provide a unique resource for the community to further explore the temporal regulation of gene expression during ER stress in vivo.

Dataset Information

A high resolution genome-wide scan of HNF4? recognition sites infers a regulatory gene network in colon cancer.

Publications

A high resolution genome-wide scan of HNF4α recognition sites infers a regulatory gene network in colon cancer.

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