Mitogen-activated protein kinase-mediated disruption of enhancer-promoter communication inhibits hepatocyte nuclear factor 4alpha expression.
Hepatocyte nuclear factor 4 (HNF-4) is a key member of the transcription factor network regulating hepatocyte differentiation and function. Activation of the HNF-4 gene involves physical interaction between a distant enhancer and the proximal promoter region, bound by distinct sets of transcription factors. Here we report that, upon mitogen-activated protein (MAP) kinase activation, HNF-4 expression is downregulated in human hepatoma cells. This effect is mediated by the loss of CEBPalpha expression. During MAP kinase signaling, the recruitment of HNF-3beta and HNF-1alpha to the HNF-4 enhancer and RNA polymerase II to the proximal HNF-4 promoter was compromised. CBP, Brg1, and TFIIB were also dissociated from the HNF-4 regulatory regions, and the enhancer-promoter complex was disrupted. Interestingly, the extent of nucleosome acetylation did not decrease at either regulatory region, and HNF-6 and HNF-1alpha, as well as components of the TFIID, remained associated with the proximal promoter during the repressed state. The results point to an absolute requirement of enhancer-promoter communication for maintaining the active state of the HNF-4 gene and provide evidence for a molecular bookmarking mechanism, which may contribute to the prevention of permanent silencing of the locus during the repressed state.
Hatzis
Pantelis
P
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, Herakleion, Crete, Greece.
Kyrmizi
Irene
I
Talianidis
Iannis
I
D000107:Acetylation / Q000187:drug effects; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000172:deficiency / Q000235:genetics; D002478:Cells, Cultured; D004265:DNA Helicases; D015536:Down-Regulation / Q000187:drug effects; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D004789:Enzyme Activation / Q000187:drug effects; D051557:Hepatocyte Nuclear Factor 4 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D034622:RNA Interference; D012319:RNA Polymerase II / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism
D022763:CCAAT-Enhancer-Binding Protein-alpha; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D006657:Histones; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D019950:Mitogen-Activated Protein Kinase 1; D012319:RNA Polymerase II; C084108:SMARCA4 protein, human; D004265:DNA Helicases; D013755:Tetradecanoylphorbol Acetate