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Homo sapiens
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Mus musculus
Homo sapiens
Mus musculus
Transcription Factor Encyclopedia  BETA
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Mutations in the human HNF4A gene lead to Maturity Onset Diabetes of the Young 1 (MODY1), a form of type 2 diabetes that patients develop around 20 to 40 years of age [1]. No homozygous mutations in human HNF4A have been reported, consistent with the embryonic lethality in mouse [2]. Infants heterozygous for HNF4A may exhibit macrosomia (high weight), hyperinsulinemia and hypoglycemia at birth, and it has been recommended that newborns with those symptoms, and a family history of diabetes, be screened for mutations in HNF4A [3][4].

Dozens of mutations (and SNPs) associated with diabetes have been mapped in the coding region of HNF4A as well as the P2 but not the P1 promoter, consistent with the P2 promoter driving expression of HNF4α in the beta cells of the pancreas [5][6].

Tissue-specific knockouts of the Hnf4a gene in mice have been created in liver, colon and pancreatic beta cells. The embryonic liver-specific knockout shows that HNF4α is required for the initial epithelial transformation of the fetal liver [7][8]. The adult liver-specific knockout indicates that HNF4α is required for maintenance of the hepatic phenotype, including lipid homeostasis [9]. The mice have a fatty liver and die within 6 weeks. Intestine/colon-specific knockouts in both the embryo and the adult verify that HNF4α is also required for the development and proper functioning of the gut [10][11][12][13]; lower levels of HNF4α have also been noted in humans with inflammatory bowel (Crohn's) disease as well as a mouse model for experimental colitis [14][12]. Two beta-cell-specific knockouts confirmed a role for HNF4α in regulating the insulin secretion pathway, although some discrepancies were noted [15][16].

In contrast to humans, mice heterozygous for HNF4α do not show signs of diabetes. The reason for this is not known. [13][12]

  1. Yamagata K et al. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1) Nature, 384(6608):458-60. (PMID 8945471)
  2. Chen WS et al. Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos. Genes Dev., 8(20):2466-77. (PMID 7958910)
  3. Pearson ER et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med., 4(4):e118. (PMID 17407387)
  4. Kapoor RR et al. Persistent hyperinsulinemic hypoglycemia and maturity-onset diabetes of the young due to heterozygous HNF4A mutations. Diabetes, 57(6):1659-63. (PMID 18268044)
  5. Ellard S and Colclough K. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha (HNF1A) and 4 alpha (HNF4A) in maturity-onset diabetes of the young. Hum. Mutat., 27(9):854-69. (PMID 16917892)
  6. Ryffel GU. Mutations in the human genes encoding the transcription factors of the hepatocyte nuclear factor (HNF)1 and HNF4 families: functional and pathological consequences. J. Mol. Endocrinol., 27(1):11-29. (PMID 11463573)
  7. Parviz F et al. Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat. Genet., 34(3):292-6. (PMID 12808453)
  8. Battle MA et al. Hepatocyte nuclear factor 4alpha orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver. Proc. Natl. Acad. Sci. U.S.A., 103(22):8419-24. (PMID 16714383)
  1. Hayhurst GP et al. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol. Cell. Biol., 21(4):1393-403. (PMID 11158324)
  2. Garrison WD et al. Hepatocyte nuclear factor 4alpha is essential for embryonic development of the mouse colon. Gastroenterology, 130(4):1207-20. (PMID 16618389)
  3. Babeu JP et al. Hepatocyte nuclear factor 4alpha contributes to an intestinal epithelial phenotype in vitro and plays a partial role in mouse intestinal epithelium differentiation. Am. J. Physiol. Gastrointest. Liver Physiol., 297(1):G124-34. (PMID 19389805)
  4. Darsigny M et al. Loss of hepatocyte-nuclear-factor-4alpha affects colonic ion transport and causes chronic inflammation resembling inflammatory bowel disease in mice. PLoS ONE, 4(10):e7609. (PMID 19898610)
  5. Cattin AL et al. Hepatocyte nuclear factor 4alpha, a key factor for homeostasis, cell architecture, and barrier function of the adult intestinal epithelium. Mol. Cell. Biol., 29(23):6294-308. (PMID 19805521)
  6. Ahn SH et al. Hepatocyte nuclear factor 4alpha in the intestinal epithelial cells protects against inflammatory bowel disease. Inflamm. Bowel Dis., 14(7):908-20. (PMID 18338782)
  7. Miura A et al. Hepatocyte nuclear factor-4alpha is essential for glucose-stimulated insulin secretion by pancreatic beta-cells. J. Biol. Chem., 281(8):5246-57. (PMID 16377800)
  8. Gupta RK et al. The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J. Clin. Invest., 115(4):1006-15. (PMID 15761495)
MeSH cloud (automatically populated)
About this section
The MeSH cloud below displays MeSH terms that are associated with this transcription factor. The physical size of the terms reflect the significance of their association with the transcription factor as determined by the Fisher's Exact Test. It should be noted that these associations do not necessarily imply a positive correlation between the described MeSH term and this transcription factor. For instance, if the MeSH term "apoptosis" occurs, it may indicate that this transcription factor can induce apoptosis (positive correlation), or prevent apoptosis (negative correlation). Methods: The transcription factor is mapped to a set of Pubmed publications through the gene-to-pubmed association as provided by NCBI. Then, a collection of MeSH terms associated with the papers are compiled, along with the frequency of each MeSH term. The Fisher's Exact Test is conducted on the frequency of each term in the collection, versus its average frequency, to determine its significance in the collection. More information on MeSH can be found on the MeSH homepage.
MeSH term Fisher's exact p-value
1 Diabetes Mellitus, Type 2 8.3 x 10-144
2 Genetic Predisposition to Disease 3.0 x 10-28
3 Carcinoma, Hepatocellular 3.6 x 10-17
4 Fetal Macrosomia 6.4 x 10-7
5 Diabetes Mellitus, Type 1 3.8 x 10-6
6 Glucose Intolerance 1.9 x 10-5
7 Diabetic Nephropathies 0.0010
8 Persistent Hyperinsulinemia Hypoglycemia of Infancy 0.0015
9 Metabolic Syndrome X 0.0064
10 Cystadenocarcinoma, Mucinous 0.0078
11 Cystadenoma, Mucinous 0.010
12 Hepatoblastoma 0.012
13 Prediabetic State 0.030
14 Stomach Neoplasms 0.041
MeSH term Fisher's exact p-value
1 Diabetes Mellitus, Type 2 8.3 x 10-144
2 Glucose Metabolism Disorders 1.8 x 10-103
3 Diabetes Mellitus 2.8 x 10-100
4 Metabolic Diseases 1.0 x 10-71
5 Endocrine System Diseases 1.8 x 10-67
6 Nutritional and Metabolic Diseases 1.5 x 10-63
7 Genetic Predisposition to Disease 3.0 x 10-28
8 Disease Susceptibility 9.0 x 10-27
9 Carcinoma, Hepatocellular 3.6 x 10-17
10 Diabetes, Gestational 2.5 x 10-13
11 Liver Neoplasms 3.4 x 10-13
12 Adenocarcinoma 1.2 x 10-11
13 Hyperinsulinism 3.0 x 10-8
14 Disease Attributes 4.9 x 10-8
15 Digestive System Neoplasms 4.9 x 10-8
16 Carcinoma 1.4 x 10-7
17 Fetal Macrosomia 6.4 x 10-7
18 Liver Diseases 7.4 x 10-7
19 Diabetes Mellitus, Type 1 3.8 x 10-6
20 Neoplasms, Glandular and Epithelial 1.3 x 10-5
21 Glucose Intolerance 1.9 x 10-5
22 Insulin Resistance 6.0 x 10-5
23 Pregnancy in Diabetics 0.00028
24 Diabetes Complications 0.00067
25 Diabetic Nephropathies 0.0010
26 Persistent Hyperinsulinemia Hypoglycemia of Infancy 0.0015
27 Hypoglycemia 0.0016
28 Hyperglycemia 0.0016
29 Birth Weight 0.0055
30 Metabolic Syndrome X 0.0064
31 Cystadenocarcinoma, Mucinous 0.0078
32 Cystadenoma, Mucinous 0.010
33 Hepatoblastoma 0.012
34 Digestive System Diseases 0.013
35 Neoplasms, Cystic, Mucinous, and Serous 0.018
36 Gastrointestinal Neoplasms 0.023
37 Fetal Diseases 0.025
38 Neoplasms by Site 0.028
39 Prediabetic State 0.030
40 Stomach Neoplasms 0.041
41 Neoplasms by Histologic Type 0.048
MGI mammalian phenotype terms (automatically populated)
no abnormal phenotype detected (MP:0002169) abnormal liver morphology (MP:0000598) abnormal hepatocyte morphology (MP:0000607) abnormal liver development (MP:0000596) dissociated hepatocytes (MP:0000608) decreased glycogen level (MP:0005439) abnormal embryogenesis/ development (MP:0001672) abnormal embryonic tissue morphology (MP:0002085) abnormal extraembryonic tissue morphology (MP:0002086) abnormal gastrulation (MP:0001695) abnormal primitive streak formation (MP:0002230) abnormal ectoderm development (MP:0001675) abnormal yolk sac morphology (MP:0001718) absent mesoderm (MP:0001683) absent amnion (MP:0005030) absent allantois (MP:0003087) embryonic lethality during organogenesis (MP:0006207) increased ectoderm apoptosis (MP:0003895) embryonic growth retardation (MP:0003984) absent chorion (MP:0009593) impaired glucose tolerance (MP:0005293) abnormal lipid homeostasis (MP:0002118) increased circulating ketone body level (MP:0002575) hepatic steatosis (MP:0002628) decreased circulating triglyceride level (MP:0002644) decreased circulating free fatty acid level (MP:0002702) decreased circulating cholesterol level (MP:0005179) increased circulating bilirubin level (MP:0005344) hypokalemia (MP:0004119) hypoferremia (MP:0004151) decreased circulating insulin level (MP:0002727) abnormal channel response (MP:0003484) prenatal lethality (MP:0002080) premature death (MP:0002083) enlarged liver (MP:0000599) weight loss (MP:0001263) decreased circulating HDL cholesterol level (MP:0000186) decreased embryo size (MP:0001698) increased apoptosis (MP:0006042)