Control of pancreas and liver gene expression by HNF transcription factors.
The transcriptional regulatory networks that specify and maintain human tissue diversity are largely uncharted. To gain insight into this circuitry, we used chromatin immunoprecipitation combined with promoter microarrays to identify systematically the genes occupied by the transcriptional regulators HNF1alpha, HNF4alpha, and HNF6, together with RNA polymerase II, in human liver and pancreatic islets. We identified tissue-specific regulatory circuits formed by HNF1alpha, HNF4alpha, and HNF6 with other transcription factors, revealing how these factors function as master regulators of hepatocyte and islet transcription. Our results suggest how misregulation of HNF4alpha can contribute to type 2 diabetes.
Odom
Duncan T
DT
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Zizlsperger
Nora
N
Gordon
D Benjamin
DB
Bell
George W
GW
Rinaldi
Nicola J
NJ
Murray
Heather L
HL
Volkert
Tom L
TL
Schreiber
Jörg
J
Rolfe
P Alexander
PA
Gifford
David K
DK
Fraenkel
Ernest
E
Bell
Graeme I
GI
Young
Richard A
RA
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050260:Carbohydrate Metabolism; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015894:Genome, Human; D005943:Gluconeogenesis; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D051559:Hepatocyte Nuclear Factor 6; D022781:Hepatocytes / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism*; D050356:Lipid Metabolism; D009687:Nuclear Proteins; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000378:metabolism*; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins; C403128:MLX protein, human; D009687:Nuclear Proteins; C496605:ONECUT1 protein, human; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D012319:RNA Polymerase II