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A high resolution genome-wide scan of HNF4alpha recognition sites infers a regulatory gene network in colon cancer

: Weltmeier, F.; Borlak, J.

Postprint urn:nbn:de:0011-n-1782250 (2.0 MByte PDF)
MD5 Fingerprint: 3297405f2d930d9a83b03e10a300caf9
Erstellt am: 1.9.2011

PLoS one. Online journal 6 (2011), Nr.7, Art. e21667, 14 S.
ISSN: 1932-6203
Zeitschriftenaufsatz, Elektronische Publikation
Fraunhofer ITEM ()

The hepatic nuclear factor HNF4alpha 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 HNF4alpha. More than 90% of HNF4alpha 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 ERalpha, AP1, GATA and HNF1alpha 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 HNF4alpha. Evidence is presented for nuclear receptor cross-talk of HNF4alpha and estrogen receptor ? that is recapitulated at the sequence level. Remarkably, the Y-chromosome is devoid of HNF4alpha binding sites. The functional importance of enrichment sites was confirmed in genome-wide gene expression studies at varying HNF4alpha protein levels. Taken collectively, a genome-wide scan of HNF4alpha binding sites is reported to better understand basic mechanisms of transcriptional control of HNF4alpha targeted genes. Novel promoter distal binding sites are identified which form an enhanceosome thereby facilitating RNA processing events.