title: Hepatocyte nuclear factor 1 coordinates multiple processes in a model of intestinal epithelial cell function.
abstract: Mutations in hepatocyte nuclear factor 1 transcription factors (HNF1α/β) are associated with diabetes. These factors are well studied in the liver, pancreas and kidney, where they direct tissue-specific gene regulation. However, they also have an important role in the biology of many other tissues, including the intestine. We investigated the transcriptional network governed by HNF1 in an intestinal epithelial cell line (Caco2). We used chromatin immunoprecipitation followed by direct sequencing (ChIP-seq) to identify HNF1 binding sites genome-wide. Direct targets of HNF1 were validated using conventional ChIP assays and confirmed by siRNA-mediated depletion of HNF1, followed by RT-qPCR. Gene ontology process enrichment analysis of the HNF1 targets identified multiple processes with a role in intestinal epithelial cell function, including properties of the cell membrane, cellular response to hormones, and regulation of biosynthetic processes. Approximately 50% of HNF1 binding sites were also occupied by other members of the intestinal transcriptional network, including hepatocyte nuclear factor 4A (HNF4A), caudal type homeobox 2 (CDX2), and forkhead box A2 (FOXA2). Depletion of HNF1 in Caco2 cells increases FOXA2 abundance and decreases levels of CDX2, illustrating the coordinated activities of the network. These data suggest that HNF1 plays an important role in regulating intestinal epithelial cell function, both directly and through interactions with other intestinal transcription factors.
authors: Human Molecular Genetics Program, Lurie Children's Research Center, Chicago, IL 60614, USA; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Rui
authors: R
authors: Yang
authors: Human Molecular Genetics Program, Lurie Children's Research Center, Chicago, IL 60614, USA; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Jenny L
authors: JL
authors: Kerschner
authors: Human Molecular Genetics Program, Lurie Children's Research Center, Chicago, IL 60614, USA; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: ann-harris@northwestern.edu.
authors: Ann
authors: A
authors: Harris
mesh_terms: D001665:Binding Sites; D000071616:CDX2 Transcription Factor; D018938:Caco-2 Cells; D003920:Diabetes Mellitus / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism*; D015894:Genome, Human; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics* / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000096:biosynthesis / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000096:biosynthesis / Q000378:metabolism; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding; D060066:Protein Interaction Maps / Q000235:genetics*
chemical_list: D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C496502:FOXA2 protein, human; C496487:HNF1A protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; D018398:Homeodomain Proteins; D051542:Hepatocyte Nuclear Factor 3-beta
keywords: Glucose transport; HNF1; Intestinal epithelium; Transcriptional network