BioPAX pathway converted from "HNF1a regulates Hnf4a" in the Reactome database. HNF1a regulates Hnf4a HNF1a regulates Hnf4a Hnf1a was shown to bind the Hnf4a promoter by chromatin immunoprecipitation (Boj et al, 2001). Genetic evidence exists that Hnf1a regulates Hnf4a in Hnf1alpha -/- mice (Boj et al, 2001, Shih et al 2001). This is supported by human genetic evidence that a mutation in the Hnf1 binding site of the Hnf4a P2 promoter causes a similar subtype of diabetes as mutations in the coding region of Hnf4a (Hansen et al, 2002). Authored: Ferrer, J, Tello-Ruiz, MK, 2008-05-23 Reviewed: Jensen, J, 2008-05-12 21:46:53 Edited: Tello-Ruiz, MK, 2006-12-19 19:02:30 Reactome DB_ID: 189782 1 cytosol GO 0005829 UniProt:P49698 Hnf4a Hnf4a Nr2a1 Tcf14 Hnf4 Hnf4a Hnf-4 FUNCTION Transcriptional regulator which controls the expression of hepatic genes during the transition of endodermal cells to hepatic progenitor cells, facilitatating the recruitment of RNA pol II to the promoters of target genes (By similarity). Activates the transcription of CYP2C38 (PubMed:30555544). Represses the CLOCK-ARNTL/BMAL1 transcriptional activity and is essential for circadian rhythm maintenance and period regulation in the liver and colon cells (PubMed:30530698).SUBUNIT Homodimerization is required for HNF4-alpha to bind to its recognition site (By similarity). Interacts with CLOCK, ARNTL and PER1 (By similarity). Interacts with PER2 (PubMed:20159955). Interacts with CRY1 and CRY2 (PubMed:28751364). Interacts with NR0B2/SHP; the resulting heterodimer is transcriptionnally inactive (By similarity). Interacts with DDX3X; this interaction disrupts the interaction between HNF4 and NR0B2 that forms inactive heterodimers and enhances the formation of active HNF4 homodimers (By similarity).TISSUE SPECIFICITY Expressed in the liver, pancreas and colon in a circadian manner.DOMAIN The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.PTM Phosphorylated on tyrosine residue(s); phosphorylation is important for its DNA-binding activity. Phosphorylation may directly or indirectly play a regulatory role in the subnuclear distribution. Phosphorylation at Ser-313 by AMPK reduces the ability to form homodimers and bind DNA (By similarity).PTM Acetylation at Lys-458 lowers transcriptional activation by about two-fold.DISRUPTION PHENOTYPE Pancreatic beta-cells-specific knockout results in hyperinsulinemia and hypoglycemia.MISCELLANEOUS Binds fatty acids.SIMILARITY Belongs to the nuclear hormone receptor family. NR2 subfamily. Reactome Mus musculus NCBI Taxonomy 10090 UniProt P49698 Reactome Database ID Release 83 186663 Database identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome R-MMU-186663 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: 11679424 Pubmed 2001 Loss of HNF-1alpha function in mice leads to abnormal expression of genes involved in pancreatic islet development and metabolism Shih, DQ Screenan, S Munoz, KN Philipson, L Pontoglio, M Yaniv, M Polonsky, KS Stoffel, M Diabetes 50:2472-80 11717395 Pubmed 2001 A transcription factor regulatory circuit in differentiated pancreatic cells Boj, SF Parrizas, M Maestro, MA Ferrer, Jorge Proc Natl Acad Sci U S A 98:14481-6 12235114 Pubmed 2002 Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function Hansen, SK Parrizas, M Jensen, ML Pruhova, S Ek, J Boj, SF Johansen, A Maestro, MA Rivera, F Eiberg, H Andel, M Lebl, J Pedersen, O Ferrer, Jorge Hansen, T J Clin Invest 110:827-33 ACTIVATION Reactome Database ID Release 83 189775 Database identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome R-MMU-189775 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome DB_ID: 187289 nucleoplasm GO 0005654 UniProt:P22361 Hnf1a Hnf1a Hnf-1a Hnf1a Tcf1 Hnf-1 FUNCTION Transcriptional activator that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver (PubMed:19289501). Binds to the inverted palindrome 5'-GTTAATNATTAAC-3' (PubMed:10966642). Activates the transcription of CYP1A2, CYP2E1 and CYP3A11 (PubMed:30555544).SUBUNIT Binds DNA as a dimer (PubMed:11106484, PubMed:11439029). Heterotetramer with PCBD1; formed by a dimer of dimers (PubMed:10966642). Interacts with PCBD1 (By similarity). Interacts with BHLHE41 (PubMed:30555544).TISSUE SPECIFICITY Liver.DISRUPTION PHENOTYPE Mice are born at less than half of the expected frequency. Neonates are slightly smaller than normal and do not grow normally. After 5 weeks mice weigh only 50 to 60% as much as their littermates. Mice develop non-insulin-dependent diabetes mellitus (NIDDM) 2 weeks after birth. Mice exhibit elevated levels of blood glucose, combined with reduced blood levels of insulin and insulin-like growth factor I (IGFI). Males and females are sterile.SIMILARITY Belongs to the HNF1 homeobox family. UniProt P22361