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FLASH GENE

Symbol

HNF4A

contributors: mct/npt/pgu - updated : 28-02-2019

HGNC name	hepatocyte nuclear factor 4, alpha
HGNC id	5024

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	30.11 kb     10 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site   enhancer

MAPPING

cloned

linked

N

status

confirmed

Map	cen - D20S101 - SRC - PLCG1 - HNF4A - D20S17 - D20S75 - D20S109 - qter

RNA

TRANSCRIPTS	type	messenger

text	with the alternatively spliced isoforms HNF4A, HNF4A2, HNF4A4

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_178849 10 - 3209 NP_849180 - 464 - 1998 9852068 NM_000457 10 - 3239 NP_000448 - 474 - 1998 9852068 NM_178850 8 - 1600 NP_849181 - 417 - 1998 9852068 NM_175914 10 - 1369 NP_787110 - 452 - 1998 9852068 NM_001030003 10 - 1339 NP_001025174 - 442 - 1998 9852068 NM_001030004 8 - 1192 NP_001025175 - 395 - 1998 9852068

EXPRESSION

Type	restricted

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine large intestine colon   moderately Homo sapiens   intestine small intestine duodenum   highly Homo sapiens   liver       moderately Homo sapiens Endocrine pancreas       moderately Homo sapiens respiratory lung bronchi       Urinary kidney       moderately Homo sapiens   kidney tubule convoluted tubule proximal tubule   Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial secretory glandular endocrine   Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Digestive epithelial cell Homo sapiens Endocrine islet cell (alpha,beta...) Homo sapiens Urinary epithelial cell Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N terminal transactivation domain
	a DNA binding protein
	a potential ligand binding and dimerization domain
	a second transactivation domain

mono polymer

homomer , dimer

HOMOLOGY

Homologene

FAMILY	nuclear hormone receptor family
	NR2 subfamily

CATEGORY

transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus,nucleoplasm
	intracellular,nucleus,chromatin/chromosome

basic FUNCTION	transcription factor 4, controlling the development of hepatic epithelium and liver morphogenesis
	sex hormones-binding globulin
	plays an essential role in the development and function of vertebrate organs, including hepatocytes and pancreatic beta-cells by regulating expression of multiple genes involved in organ development, nutrient transport, and diverse metabolic pathways
	having a function in the regulation of intestinal vitamin A absorption and metabolism
	modulates Wnt/beta-catenin signaling and controls intestinal epithelium homeostasis, cell function, and cell architecture
	fundamental role of dynamic regulatory interactions between HNF4A, HES6, PPARA, and PPARG in the coordinated expression of genes involved in fatty acid transport and metabolism
	plays a central role in the transdifferentiation process of hematopoietic cells into hepatocytes
	might be important for intestinal glycolipid metabolism
	may play a key role in intestinal lipid metabolism as well as intestinal anti-oxidative and anti-inflammatory defense mechanisms
	hepatic HNF4a is essential for controlling the basal expression of numerous genes involved in lipid metabolism and is indispensable for maintaining normal lipid homeostasis
	controls the expression of many critical metabolic pathways, and the Mediator complex occupies a central role in recruiting RNA polymerase II (Pol II) to these gene promoters
	acting not only as a global player in many cellular processes, but also as one of the components of inflammatory response in the liver
	both HNF4A activator and repressor functions are necessary for the identity of hepatocytes
	essential for specification of hepatic progenitor cells by establishing the expression of the network of transcription factors that controls the onset of hepatocyte cell fat
	HNF4A is likely involved in maintenance of the ER

CELLULAR PROCESS

nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

carbohydrate

signaling

a component

INTERACTION

DNA

binding

RNA

small molecule

protein	interacting with HNF1A for regulation of gene activity and chromatin structure of serpin cluster (PI)
	interacting with CYP8B1 for its transcription and its repression by bile acids
	interaction with RBP2 (regulates RBP2)
	interacts with other hepatocyte nuclear factors in regulating transthyretin gene expression
	interacting with MED25 (MED25, an associated member of the Mediator complex, is required for the association of HNF4A with Mediator, its several cofactors, and RNA Pol II)
	HNF4A, in cooperation with its target HNF1A, directly inhibits transcription of the EMT (epithelial-to-mesenchymal transition) master regulatory genes SNAI1, SNAI2, and HMGA2 and of several mesenchymal markers
	ANKS4B is a target of HNF4A in pancreatic beta-cells
	HES6 subsequently represses HNF4A (HNF-4A)-activated PPARG gene expression by direct inhibition of HNF4A transcriptional activity
	HNF4A regulates liver type fatty acid binding protein (FABP1) gene expression
	NR3C1-induced expression of HNF4A may likely contribute to indirect SLC22A1 gene up-regulation by dexamethasone in primary human hepatocytes, but not in hepatocyte-derived tumor cell lines
	HNF4A contributes to the transcriptional regulation of SLC2A9
	Hippo signaling may affect hepatocyte differentiation by influencing HNF4A and FOXA2 interactions with temporal enhancers
	HNF4A is a regulatory factor that bound endogenous CLDN7 promoter in differentiating intestinal epithelial cell (IEC) and stimulated CLDN7 promoter activity
	HNF4A is a major transcriptional regulator of SLC22A9
	HNF4A is a vital transcription factor in the SHBG synthesis process

cell & other

REGULATION

activated by

GATA6 for establishment of the endodermally derived bronchial epithelium

inhibited by

the activation of the ERK1/2 cascade

Other	coexpressed with TCF1
	multiple post-translational modifications were identified in HNF4A and unexpected role of an HNF4A acetylation could be uncovered

ASSOCIATED DISORDERS

corresponding disease(s)

MODY1

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional germinal mutation       in diazoxide responsive congenital hyperinsulinism (CHI) constitutional germinal mutation     loss of function dominant inactivating mutations in children with transient, diazoxide-responsive hyperinsulinism (HI) without clear history of perinatal stress

Susceptibility

to type 2 diabetes mellitus

Variant & Polymorphism SNP	associated with the risk of type 2 diabetes mellitus
	late-onset diabetes mutation, -192C>G, impair the function of the HNF4A P2

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed digestive liver   may serve as novel targets for the treatment of liver fibrosis

ANIMAL & CELL MODELS

in the intestines of adult mice, loss of Hnf-4alpha led to an increased proliferation in crypts and to an increased expression of several genes controlled by the Wnt/beta-catenin system