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HNF4A (Hepatocyte Nuclear Factor 4 alpha)

Written2016-06Sinem Tunçer, Sreeparna Banerjee
Department of Biological Sciences, Middle East Technical University, Ankara, Turkey

Abstract Hepatocyte nuclear factor 4 alpha (HNF4A) also known as NR2A1 (Nuclear Receptor Subfamily 2, group A, member 1) is a member of the nuclear receptor (NR) superfamily of ligand-dependent transcription factors. The encoded protein controls the expression of several genes, especially those that play distinct roles in development, differentiation, embryogenesis and organogenesis.

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Identity

HGNC (Hugo) HNF4A
LocusID (NCBI) 3172
Atlas_Id 44014
Location The human HNF4A gene is located on 20q12-q13.1  [Link to chromosome band 4]
Location_base_pair Starts at 43029896 and ends at 43061485 bp from pter ( according to hg19-Feb_2009)  [Mapping HNF4A.png]

DNA/RNA

 
  Figure 1 HNF4A transcripts. HNF4A contains two distinct promoters (P1 and P2) that drive expression of 9 known isoforms (α1 to α9) of the gene. Transcription through the P1 promoter allows transcription starting from exon 1 (B) coding for the N-terminal domain of HNF4A, designated as AF-1. Transcription through the P2 promoter allows the inclusion of exon 1 (A) but the exclusion of the exon 1 (B). Although alternative splicing of exon 1 (B) modifies only A/B domain of the P1 isoforms, F domains of both isoforms are modified by alternative splicing of the last exons. DBD: DNA binding domain; LBD: Ligand binding domain; AF-1: Activating function-1; AF-2: Activating function-2 (Modified from Babeu and Boudreau, 2014).
Description The human HNF4A gene spans ~77 kb.
Transcription The HNF4A gene is composed of thirteen exons and contains two promoters, P1 and P2, which can drive the expression of many splice variants (HNF4A1-HNF4A9) that differ in the variable A/B and F domains (Harries et al., 2008). The variants derived from the P1 and P2 promoters are referred to as HNF4A1-HNF4A6 and HNF4A7-HNF4A9, respectively (Erdmann et al., 2007).
The different promoters are used in different tissues and at different times during development, and the encoded protein controls the expression of several genes. Multiple isoforms are proposed to exist in mammals and are thought to have different physiological roles in development and differentiation (Walesky and Apte, 2015).

Protein

Description Domain structure and DNA binding
HNF4A consists of six structural domains named A-F that are responsible for specific functions: an N-terminal activation domain (AF-1, also referred to as A/B domain); a zinc finger domain that serves as the DNA-binding domain (DBD; C domain) which is highly conserved among NRs; a putative ligand binding domain (LBD; E domain); and a C-terminal domain which functions in homodimerization and activation (AF-2), and a repressor region (F domain) that inhibits access of coactivators to AF-2, and possibly to other regions (Walesky and Apte, 2015). The DBD consists of two zinc fingers, and 12 alpha helices that create a hydrophobic pocket for ligand binding (Duda et al., 2004) (Figure 2).
HNF4A binds DNA regulatory elements as a homodimer. E domain (Ligand Binding Domain-LBD) appears to be critical for homodimerization and to play a role in preventing heterodimerization with other NRs such as RXR or RAR (Bogan et al., 2000). HNF4A binds DNA response elements consisting of direct repeats. It can also bind several different co-activators (such as GRIP1, NCOA1, NCOA2, NCOA3, (SRC1, 2 and 3), CREBBP (CBP/P300), PPARGC1A (PGC1)) (MartÍnez-Jiménez et al., 2006).
 
  Figure 2 HNF4A domains. AF-1: activation function; DBD: DNA binding function; LBD: ligand binding function; F domain: repressor function that inhibits access of coactivators to NCOA5 (AF-2) which function in homodimerization and activation. H: hinge region.
Expression Multiple HNF4A isoforms exist in humans and are suggested to have different physiological roles in development and transcriptional regulation of target genes (Figure 1). HNF4A1 and 2 isoforms from the P1 promoter are expressed in the liver (hepatocytes), kidneys, small intestine and colon. HNF4A3 and 4 are expressed in human liver. P2 promoter-driven HNF4A7 and 8 are expressed in the fetal liver and adult pancreas (β-cells) and to a lesser extent in the adult liver (bile ducts), small intestine, colon and stomach. HNF4A isoforms from both the P1 and P2 promoter were also reported to be expressed in the epididymis (Tanaka et al., 2006). However, not much is known about the developmental and physiological relevance of the HNF4A isoforms (Boyd et al., 2009). In addition to several different isoforms produced from the HNF4A gene by different promoter usage and alternative splicing, the 3'UTR of the gene was also reported to control HNF4A expression (Wirsing et al., 2011).
Localisation Localized primarily in the nucleus.
Function HNF4A can exist in an unliganded form, or may bind to linoleic acid (LA), an essential fatty acid (Yuan et al., 2009). Although it is not yet clear whether ligand binding affects the function of HNF4A, the HNF4A transcriptional activity is regulated at several different levels. Most prominent among the post-translational modifications of HNF4A is phosphorylation which occurs mainly at serine and to a lesser extent at threonine residues (Jiang et al., 1997). Between the kinases, PRKACA (protein kinase A, PKA) dependent phosphorylation of HNF4A was reported to inhibit recruitment to target genes (You et al., 2002). On the other hand, activation of MAP kinase pathway was shown to down-regulate HNF4A transcription (Reddy et al., 1999). AMP-activated protein kinase was also implicated in the regulation of HNF4A activity by inhibiting dimer formation and decreasing protein stability (Hong et al., 2003). p38 kinase-mediated Ser158 phosphorylation was also shown to increase DNA binding and transactivation potential of HNF4A (Guo et al., 2006), and Ser78 phosphorylation of HNF4A by PRKCB (protein kinase C, PKC) was shown to down-regulate HNF4A protein level via the proteasome pathway (Sun et al., 2007).
Acetylation was also implicated in the regulation of HNF4A function (Soutoglou et al., 2000; Yokoyama et al., 2011). Soutoglou et al. showed that CREB-binding protein (CBP) acetylates HNF4A on lysine residues within the nuclear localization sequence, and increase nuclear retention and target gene activation by HNF4A (Soutoglou et al., 2000).
Methylation and SUMOylation are the other post-translational mechanisms that regulate HNF4A activity. Methylation of the DNA-binding domain of HNF4A by PRMT1 (Protein Arginine Methyltransferase 1), whose methylation activity on HIST4H4 (histone H4 )strongly correlates with the induction of HNF4A target genes in differentiating enterocytes, increased transcriptional activity of HNF4A (Barrero and Malik, 2006). SUMOylation is the other mechanism that regulates HNF4A protein stability and potentially DNA binding activity (Zhou et al., 2012).
As a transcription factor, HNF4A was first identified to be bound to DNA sites required for the transcription of two liver-specific genes: TTR (transthyretin) and APO3 (apolipoprotein CIII) (Sladek et al., 1990). An increasing number of studies implicate a vital role of HNF4A in the development of the liver, intestine and pancreas, differentiation and homeostasis (Figure 3).
Liver
HNF4A has been shown to be required for hepatocyte differentiation and development of the liver. The expression of HNF4A mRNA in post-implantation mouse embryos was found in the primary endoderm starting at day 4.5. From day 8.5, HNF4A mRNA was detected in embryonic tissues in the liver diverticulum and the hindgut. At later times, HNF4A transcripts were found in the mesonephric tubules, pancreas, stomach, intestine, and in the metanephric tubules of the developing kidney (Duncan et al., 1994). Additionally, conditional genetic removal of HNF4A in the liver resulted in disorganization of morphological and functional differentiation in the hepatic epithelium (Parviz et al., 2003). In hepatocyte-specific knock-out model, lack of HNF4A expression in the liver caused impaired lipid metabolism and gluconeogenesis (Hayhurst et al., 2001), indicating that HNF4A controls genes involved in hepatic lipid and glucose metabolism, hereby influencing the hepatocyte metabolome (Parviz et al., 2003). On the other hand, homozygous loss of HNF4A gene resulted in embryonic lethality (Chen et al., 1994.). HNF4A was also found to be related to epithelial cell adhesion and junction formation in the fetal liver (Battle et al., 2006). Re-expression of HNF4A was shown to induce cells to reform junctions and express hepatocyte marker genes in a dedifferentiated hepatoma cell line (Späth and Weiss, 1997; Späth and Weiss, 1998). More recently, HNF4A was implicated in the differentiation of hepatic stellate cells into hepatocyte-like cells (Liu et al., 2015). Furthermore, in non-hepatic cells, ectopic over expression of HNF4A in fibroblasts induced mesenchymal to epithelial transition (EMT), indicating that HNF4A is a dominant regulator of the morphogenetic parameters that form the epithelial phenotype (Parviz et al., 2003.).
More recently, Yang et al. showed that during EMT, there is a negative feedback loop between Wnt-β-catenin signaling and HNF4A, both in vivo and in vitro. Restoring HNF4A expression was suggested as a method to inhibit invasion in hepatocellular carcinoma by preventing EMT (Yang et al., 2013).
Intestine
HNF4A plays essential roles in the intestine, particularly in epithelial cell function, differentiation and normal colon physiology (Chellappa et al., 2012).
To directly address the role of HNF4A in development of the colon, an epithelial-specific knockout model of HNF4A was created in mice by using the Cre-loxP system. Examination of the embryos revealed that HNF4A ablation disrupts development of normal crypt topology in fetal colons, and reduced goblet cell maturation (Garrison et al., 2006). In adult small intestine, HNF4A was shown to play a critical role in the homeostasis of intestinal epithelium, in the epithelial cell architecture, and in the barrier function of the intestine. Loss of intestinal HNF4A affected the Wnt/β-catenin signaling pathway, and destabilized adherens and tight junctions (Cattin et al., 2009). Recently, Vuong et al. suggested that HNF4A isoforms play distinct roles in colon cancer, which could be caused by differential interactions with the Wnt/β-catenin/TCF4 and AP-1 pathways (Vuong et al., 2015).
Importance of HNF4A in the formation of tight epithelial barrier to exert a selective barrier function in relation to apical-to-basal transport was also shown in a coculture system (Lussier et al., 2008). Besides nutrient metabolism (Black, 2007) and protection against pathogens (Laukoetter et al., 2006), another function of the epithelial barrier is the control of appropriate ion selectivity. Loss of this function can lead to deregulation of colonic inflammatory homeostasis and inflammatory bowel disease (IBD) (Darsigny et al., 2009).
HNF4A appears to play a protective role against IBD, an important risk factor for colorectal cancer. In patients with IBD, HNF4A expression was significantly decreased. Accordingly, intestine specific HNF4A-null mice exhibited increased susceptibility to dextran sulfate sodium (DSS) induced IBD with increased intestinal permeability, suggesting that HNF4A was required to protect the epithelium during experimental colitis (Ahn et al., 2008).
HNF4A was also addressed as a crucial transcription factor in the differentiation of intestinal cells. Intestine specific knockout of HNF4A in the adult mouse enhanced proliferation in crypts, and increased number of mucus secreting cells (Cattin et al., 2009). HNF4A was also shown to be involved in the regulation of genes involved in the enterocyte differentiation and in lipid metabolism (Béaslas et al., 2008; Stegmann et al. 2006; Cattin et al., 2009). To address the role of HNF4A in differentiation dependent transcription in human colonic epithelial cells, Boyd et al. performed a genome-wide identification of promoters that are occupied by HNF4A in vivo. The analysis revealed that HNF4A was mostly associated with the promoter regions involved in transport and metabolism. HNF4A was found to regulate differentiation dependent transcription by regulating the expression of HNF1A and CDX2, transcription factors necessary for the expression of many intestinal genes important in the development and differentiation program in the colon (Boyd et al., 2009).
Pancreas
HNF4A activity is essential for β-cell function through the regulation of several genes, including those involved in metabolism-secretion coupling, such as glucose transporter-2, L-pyruvate kinase, aldolase B, 2-oxoglutarate dehydrogenase E1 subunit, mitochondrial uncoupling protein-2 (Wang et al., 2000) and the potassium channel subunit Kir6.2 (Gupta et al., 2005), as well as the INS (insulin gene) (Wang et al, 2000; Bartoov-Shifman et al., 2002). In pancreatic β-cells, HNF4A maintains glucose homeostasis (Marcil et al., 2015; Wang et al., 2000). Gene expression analysis in type 2 diabetes (T2D) patients compared to normal glucose-tolerant controls revealed that HNF4A mRNA level decreased in pancreatic β-cells of T2D patients (Gunton et al., 2005). Moreover, HNF4A mutations were implicated in Mature-Onset Diabetes of the Young 1 (MODYI), a dominantly inherited atypical subgroup of T2D characterized by decreased glucose stimulated insulin secretion in pancreatic β-cells (Yamagata et al., 1996). More recently, it was suggested lack of HNF4A function disrupts Ca2+ signaling and insulin release in β-cells of patients with MODYI through altered endoplasmic reticulum (ER) Ca2+ homeostasis (Moore et al., 2016). Figure 3 HNF4A can regulate different cell functions. HNF4A is an important regulator with a strong impact on endodermal development, organ differentiation and metabolism.
 
  ntiation program in the colon (Boyd et al., 2009).
Homology HNF4A is highly conserved across species, with 100% amino acid conservation in the DNA binding domain of all mammalian HNF4A. HNF4A has been found in every animal organism examined thus far, including sponge and coral, and has been postulated to be the ancestor of the entire NR family (Bolotin et al., 2011) (Table 1 and Figure 4).
 
  Table 1 Pairwise alignment of HNF4A gene and protein sequences (in distance from human). HNF4A is highly conserved evolutionarily.
 
  Figure 4 HNF4A proteins and their conserved domain architectures. HNF4A is a member of the nuclear receptor (NR) family of transcription factors that use conserved DNA binding domains (DBDs) and ligand binding domains (LBDs).

Mutations

Note HNF4A is at the center of a complex transcriptional regulatory network and is implicated to several human diseases including diabetes (Mohlke and Boehnke, 2005), MODY1 (Ryffel, 2001), hemophilia (Reijnen et al., 1992) and hepatitis B viral infections (He et al., 2012). The HNF4A locus has been associated with high-density lipoprotein cholesterol (HDL-C) (Teslovich et al., 2010) and metabolic dyslipidemia (Suviolahti et al., 2006). Finally, since it regulates several Phase I/II and other genes in the liver, HNF4A is suggested to play a role in drug metabolism (Hwang-Verslues and Sladek, 2010). In addition, polymorphisms (Hwang-Verslues and Sladek, 2010; Ruchat et al., 2009; Marcil et al., 2015) and mutations (Ryffel, 2001) in the human HNF4A gene are associated with altered expression and transcriptional activity.
Germinal Diabetes mellitus, noninsulin-dependent (NIDDM):
In early disease onset, three mutations affecting HNF4A function were identified (D126Y; D126H; R154Q) (Aguilar-Salinas et al., 2001). In late onset, missense mutations were identified in the LBD (R323H) (Price et al., 2000) and the F domain (V393I); the latter resulted in a reduced transactivational activity (Hani et. al., 1998). V255M mutation has also been shown to reduce transactivation, albeit modestly (Mohlke and Boehnke, 2005).
Thirteen single nucleotide polymorphisms (SNPs) in the P2 promoter, three of which were identified in Pima Indians, have also been associated with T2D (Muller et al. 2005). A 7 bp deletion in the Sp1 site of the P1 promoter was identified in type II diabetic nephropathic Caucasian patients (Price et al., 2000).
Factor VII deficiency:
Homozygous mutation for a T to G transversion at nucleotide -61 position in the factor VII promoter was shown to disrupt HNF4A binding and result in a significant reduction in factor VII promoter activity (Arbini et al., 1997).
Maturity-onset diabetes of the young, type 1 (MODY1):
Mutations in the HNF4A coding region and promoter were shown to be directly implicated in MODY1 in several different human populations (Ryffel, 2001).
Two deletion mutations (F75fsdelT and K99fsdelAA) generate truncated proteins lacking part of the zinc finger domain essential for DNA binding. An in-frame insertion mutation, V328ins, located in the LBD, was suggested to alter the highly conserved structural organization of the protein. R154X and Q268X nonsense mutants retain the DNA binding domain but lack a substantial portion of the potential ligand binding part (Ryffel, 2001). R127W and E276Q missense mutations were reported to result in a significant loss of HNF4A activity (Lausen et al., 2000). The HNF4A mutations G115S (Oxombre et al., 2004.); R127W (Furuta et al., 1997); R244Q (Hara et al., 2002.); R324H (Price et al., 2000.); IVS5-2delA (Barrio et al., 2002) have also been associated with MODY1. Of note, -146T->C in the P2 promoter region was reported to be associated with MODY1 by affecting PDX1 (IPF-1) binding to DNA (Thomas et al., 2001).
Familial Hyperinsulinism due to HNF4A deficiency (FHI-HNF4A):
Familial hyperinsulinism due to HNF4A deficiency is a form of diazoxide-sensitive diffuse hyperinsulinism (DHI), characterized by macrosomia, transient or persistent hyperinsulinemic hypoglycemia (HH), responsiveness to the diazoxide and a propensity to develop MODY1 (Glaser, 2013). The transmission is autosomal dominant with variable penetrance (Pearson et al., 2007; Kapoor et al., 2008).

Implicated in

Note
Entity Gastric adenocarcinoma
Note HNF4A expression was seen in primary gastric adenocarcinomas and in metastases of gastric carcinoma to the breast, but was absent in primary breast carcinomas, and in metastases of breast carcinomas to the stomach (van der Post t al., 2014).
  

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Citation

This paper should be referenced as such :
Tunçer S, Banerjee S
HNF4A (Hepatocyte Nuclear Factor 4 alpha);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/HNF4AID44014ch20q13.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  dic(17;20)(p11.2;q11.2)

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 0 ]
  Skin: Pilomatricoma

External links

Nomenclature
HGNC (Hugo)HNF4A   5024
Cards
AtlasHNF4AID44014ch20q13
Entrez_Gene (NCBI)HNF4A  3172  hepatocyte nuclear factor 4 alpha
AliasesFRTS4; HNF4; HNF4a7; HNF4a8; 
HNF4a9; HNF4alpha; MODY; MODY1; NR2A1; NR2A21; TCF; TCF14
GeneCards (Weizmann)HNF4A
Ensembl hg19 (Hinxton)ENSG00000101076 [Gene_View]  chr20:43029896-43061485 [Contig_View]  HNF4A [Vega]
Ensembl hg38 (Hinxton)ENSG00000101076 [Gene_View]  chr20:43029896-43061485 [Contig_View]  HNF4A [Vega]
ICGC DataPortalENSG00000101076
TCGA cBioPortalHNF4A
AceView (NCBI)HNF4A
Genatlas (Paris)HNF4A
WikiGenes3172
SOURCE (Princeton)HNF4A
Genomic and cartography
GoldenPath hg19 (UCSC)HNF4A  -     chr20:43029896-43061485 +  20q13.12   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)HNF4A  -     20q13.12   [Description]    (hg38-Dec_2013)
EnsemblHNF4A - 20q13.12 [CytoView hg19]  HNF4A - 20q13.12 [CytoView hg38]
Mapping of homologs : NCBIHNF4A [Mapview hg19]  HNF4A [Mapview hg38]
OMIM125850   125853   600281   616026   
Gene and transcription
Genbank (Entrez)AB307703 AK096973 AW134564 AW935533 AY680696
RefSeq transcript (Entrez)NM_000457 NM_001030003 NM_001030004 NM_001258355 NM_001287182 NM_001287183 NM_001287184 NM_175914 NM_178849 NM_178850
RefSeq genomic (Entrez)NC_000020 NC_018931 NG_009818 NT_011362 NW_004929418
Consensus coding sequences : CCDS (NCBI)HNF4A
Cluster EST : UnigeneHs.116462 [ NCBI ]
CGAP (NCI)Hs.116462
Alternative Splicing GalleryENSG00000101076
Gene ExpressionHNF4A [ NCBI-GEO ]   HNF4A [ EBI - ARRAY_EXPRESS ]   HNF4A [ SEEK ]   HNF4A [ MEM ]
Gene Expression Viewer (FireBrowse)HNF4A [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3172
GTEX Portal (Tissue expression)HNF4A
Protein : pattern, domain, 3D structure
UniProt/SwissProtP41235 (Uniprot)
NextProtP41235  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP41235
Splice isoforms : SwissVarP41235 (Swissvar)
PhosPhoSitePlusP41235
Domaine pattern : Prosite (Expaxy)NUCLEAR_REC_DBD_1 (PS00031)    NUCLEAR_REC_DBD_2 (PS51030)   
Domains : Interpro (EBI)COUP_TF    Nucl_hrmn_rcpt_lig-bd    Nuclear_hrmn_rcpt    Znf_hrmn_rcpt    Znf_NHR/GATA   
Domain families : Pfam (Sanger)Hormone_recep (PF00104)    zf-C4 (PF00105)   
Domain families : Pfam (NCBI)pfam00104    pfam00105   
Domain families : Smart (EMBL)HOLI (SM00430)  ZnF_C4 (SM00399)  
DMDM Disease mutations3172
Blocks (Seattle)HNF4A
PDB (SRS)1PZL    3CBB    3FS1    4B7W    4IQR   
PDB (PDBSum)1PZL    3CBB    3FS1    4B7W    4IQR   
PDB (IMB)1PZL    3CBB    3FS1    4B7W    4IQR   
PDB (RSDB)1PZL    3CBB    3FS1    4B7W    4IQR   
Structural Biology KnowledgeBase1PZL    3CBB    3FS1    4B7W    4IQR   
SCOP (Structural Classification of Proteins)1PZL    3CBB    3FS1    4B7W    4IQR   
CATH (Classification of proteins structures)1PZL    3CBB    3FS1    4B7W    4IQR   
SuperfamilyP41235
Human Protein AtlasENSG00000101076
Peptide AtlasP41235
HPRD02612
IPIIPI00013196   IPI00216080   IPI00641248   IPI00412368   IPI00847265   IPI00645235   IPI00300558   IPI00945710   
Protein Interaction databases
DIP (DOE-UCLA)P41235
IntAct (EBI)P41235
FunCoupENSG00000101076
BioGRIDHNF4A
STRING (EMBL)HNF4A
ZODIACHNF4A
Ontologies - Pathways
QuickGOP41235
Ontology : AmiGOfatty-acyl-CoA binding  RNA polymerase II core promoter sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  RNA polymerase II activating transcription factor binding  DNA binding  transcription factor activity, sequence-specific DNA binding  transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding  steroid hormone receptor activity  RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding  receptor binding  fatty acid binding  protein binding  nucleus  nucleoplasm  transcription factor complex  cytoplasm  regulation of transcription from RNA polymerase II promoter  regulation of transcription from RNA polymerase II promoter  transcription initiation from RNA polymerase II promoter  ornithine metabolic process  lipid metabolic process  acyl-CoA metabolic process  xenobiotic metabolic process  establishment of tissue polarity  sex differentiation  blood coagulation  zinc ion binding  negative regulation of cell proliferation  response to glucose  regulation of gastrulation  palmitoyl-CoA hydrolase activity  regulation of lipid metabolic process  signal transduction involved in regulation of gene expression  cell differentiation  negative regulation of cell growth  intracellular receptor signaling pathway  regulation of microvillus assembly  negative regulation of protein import into nucleus, translocation  response to drug  negative regulation of tyrosine phosphorylation of Stat5 protein  glucose homeostasis  protein homodimerization activity  steroid hormone mediated signaling pathway  negative regulation of sequence-specific DNA binding transcription factor activity  transcription regulatory region DNA binding  cell-cell junction organization  positive regulation of gluconeogenesis  positive regulation of fatty acid biosynthetic process  positive regulation of transcription, DNA-templated  negative regulation of mitotic cell cycle  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  regulation of insulin secretion  response to cAMP  lipid homeostasis  phospholipid homeostasis  SMAD protein signal transduction  regulation of growth hormone receptor signaling pathway  triglyceride homeostasis  negative regulation of activation of JAK2 kinase activity  positive regulation of cholesterol homeostasis  
Ontology : EGO-EBIfatty-acyl-CoA binding  RNA polymerase II core promoter sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  RNA polymerase II activating transcription factor binding  DNA binding  transcription factor activity, sequence-specific DNA binding  transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding  steroid hormone receptor activity  RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding  receptor binding  fatty acid binding  protein binding  nucleus  nucleoplasm  transcription factor complex  cytoplasm  regulation of transcription from RNA polymerase II promoter  regulation of transcription from RNA polymerase II promoter  transcription initiation from RNA polymerase II promoter  ornithine metabolic process  lipid metabolic process  acyl-CoA metabolic process  xenobiotic metabolic process  establishment of tissue polarity  sex differentiation  blood coagulation  zinc ion binding  negative regulation of cell proliferation  response to glucose  regulation of gastrulation  palmitoyl-CoA hydrolase activity  regulation of lipid metabolic process  signal transduction involved in regulation of gene expression  cell differentiation  negative regulation of cell growth  intracellular receptor signaling pathway  regulation of microvillus assembly  negative regulation of protein import into nucleus, translocation  response to drug  negative regulation of tyrosine phosphorylation of Stat5 protein  glucose homeostasis  protein homodimerization activity  steroid hormone mediated signaling pathway  negative regulation of sequence-specific DNA binding transcription factor activity  transcription regulatory region DNA binding  cell-cell junction organization  positive regulation of gluconeogenesis  positive regulation of fatty acid biosynthetic process  positive regulation of transcription, DNA-templated  negative regulation of mitotic cell cycle  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  regulation of insulin secretion  response to cAMP  lipid homeostasis  phospholipid homeostasis  SMAD protein signal transduction  regulation of growth hormone receptor signaling pathway  triglyceride homeostasis  negative regulation of activation of JAK2 kinase activity  positive regulation of cholesterol homeostasis  
Pathways : KEGGMaturity onset diabetes of the young   
REACTOMEP41235 [protein]
REACTOME PathwaysR-HSA-383280 Nuclear Receptor transcription pathway [pathway]
NDEx NetworkHNF4A
Atlas of Cancer Signalling NetworkHNF4A
Wikipedia pathwaysHNF4A
Orthology - Evolution
OrthoDB3172
GeneTree (enSembl)ENSG00000101076
Phylogenetic Trees/Animal Genes : TreeFamHNF4A
Homologs : HomoloGeneHNF4A
Homology/Alignments : Family Browser (UCSC)HNF4A
Gene fusions - Rearrangements
Fusion : MitelmanSLCO2B1/HNF4A [11q13.4/20q13.12]  [t(11;20)(q13;q13)]  
Fusion: TCGASLCO2B1 11q13.4 HNF4A 20q13.12 KIRC
Fusion Cancer (Beijing)SFTPB [2p11.2]  -  HNF4A [20q13.12]  [FUSC002436]
Polymorphisms : SNP, variants
NCBI Variation ViewerHNF4A [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)HNF4A
dbVarHNF4A
ClinVarHNF4A
1000_GenomesHNF4A 
Exome Variant ServerHNF4A
ExAC (Exome Aggregation Consortium)HNF4A (select the gene name)
Genetic variants : HAPMAP3172
Genomic Variants (DGV)HNF4A [DGVbeta]
Mutations
ICGC Data PortalHNF4A 
TCGA Data PortalHNF4A 
Broad Tumor PortalHNF4A
OASIS PortalHNF4A [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICHNF4A 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)Monogenic Diabetes
LOVD (Leiden Open Variation Database)MSeqDR-LSDB Mitochondrial Disease Locus Specific Database
BioMutasearch HNF4A
DgiDB (Drug Gene Interaction Database)HNF4A
DoCM (Curated mutations)HNF4A (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)HNF4A (select a term)
intoGenHNF4A
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)20:43029896-43061485  ENSG00000101076
CONAN: Copy Number AnalysisHNF4A 
Mutations and Diseases : HGMDHNF4A
OMIM125850    125853    600281    616026   
MedgenHNF4A
Genetic Testing Registry HNF4A
NextProtP41235 [Medical]
TSGene3172
GENETestsHNF4A
Huge Navigator HNF4A [HugePedia]
snp3D : Map Gene to Disease3172
BioCentury BCIQHNF4A
ClinGenHNF4A
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD3172
Chemical/Pharm GKB GenePA29349
Clinical trialHNF4A
Miscellaneous
canSAR (ICR)HNF4A (select the gene name)
Probes
Litterature
PubMed401 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineHNF4A
EVEXHNF4A
GoPubMedHNF4A
iHOPHNF4A
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Sep 28 15:59:38 CEST 2016

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