Hepatocyte nuclear factors

Hepatocyte nuclear factors (HNFs) are a group of phylogenetically unrelated transcription factors that regulate the transcription of a diverse group of genes into proteins. These proteins include blood clotting factors and in addition, enzymes and transporters involved with glucose, cholesterol, and fatty acid transport and metabolism. ^{[1] [2]}

Function

As the name suggests, hepatocyte nuclear factors are expressed predominantly in the liver. However HNFs are also expressed and play important roles in a number of other tissues so that the name hepatocyte nuclear factor is somewhat misleading. Nevertheless, the liver is the only tissue in which a significant number of different HNFs are expressed at the same time. In addition, there are a number of genes which contain multiple promoter and enhancer regions each regulated by a different HNF. Furthermore, efficient expression of these genes require synergistic activation by multiple HNFs. Hence hepatocyte nuclear factors function to ensure liver specific expression of certain genes.

As is the case with many transcription factors, HNFs regulate the expression of a wide variety of target genes and therefore functions. These functions (and especially functions involving the liver) include development and metabolic homeostasis of the organism. For example, HNFs influence expression of the insulin gene as well as genes involved in glucose transport and metabolism. In embryo development, HNF4α is thought to have an important role in the development of the liver, kidney, and intestines.

Disease implication

Variants of the genes can cause several relatively rare forms of MODY, an inherited, early onset form of diabetes. Mutations in the HNF4α, HNF1α, or HNF1β genes are linked to MODY 1, MODY 3, and MODY 5 respectively. ^[3] Mutations in HNF genes are also associated with a number of others diseases including hepatic adenomas and renal cysts.

Members

The following is a list of human hepatocyte nuclear factors (see also boxes to the right for additional information about these proteins):

HNF1

Members of the HNF1 subfamily contain a POU-homeodomain and bind to DNA as homodimers.

• HNF1α/TCF1/MODY3 (related disease: MODY 3)
• HNF1β/TCF2/MODY5 (related disease: MODY 5)

hepatocyte nuclear factor 1, alpha Structure of the hepatocyte nuclear factor 1A (green cartoon) bound to DNA (magenta) based on the crystallographic coordinates PDB: 1IC8 ​. Identifiers Symbol HNF1A Alt. symbols MODY3, HNF1, LFB1, TCF1 NCBI gene 6927 HGNC 11621 OMIM 142410 PDB 1JB6 RefSeq NM_000545 UniProt P20823 Other data Locus Chr. 12 q24.3-12q24.3 Search for Structures Swiss-model Domains InterPro

hepatocyte nuclear factor 1, beta Identifiers Symbol HNF1B Alt. symbols TCF2, HNF1beta, LFB3 MODY5, VHNF1 NCBI gene 6928 HGNC 11630 OMIM 189907 PDB 2H8R RefSeq NM_000458 UniProt P35680 Other data Locus Chr. 17 q12-17q12 Search for Structures Swiss-model Domains InterPro

HNF3

The HNF3 subfamily members contain a winged helix DNA-binding domain and bind to DNA as monomers.

• HNF3α/FOXA1 (forkhead box A1)
• HNF3β/FOXA2 (forkhead box A2)
• HNF3γ/FOXA3 (forkhead box A3)

hepatocyte nuclear factor 3, alpha Identifiers Symbol FOXA1 Alt. symbols HNF3A NCBI gene 3169 HGNC 5021 OMIM 602294 RefSeq NM_004496 UniProt P55317 Other data Locus Chr. 14 q12-q13 Search for Structures Swiss-model Domains InterPro

hepatocyte nuclear factor 3, beta Identifiers Symbol FOXA2 Alt. symbols HNF3B NCBI gene 3170 HGNC 5022 OMIM 600288 RefSeq NM_021784 UniProt Q9Y261 Other data Locus Chr. 20 p1120p11 Search for Structures Swiss-model Domains InterPro

hepatocyte nuclear factor 3, gamma Identifiers Symbol FOXA3 Alt. symbols HNF3G NCBI gene 3171 HGNC 5023 OMIM 602295 RefSeq NM_004497 UniProt P55318 Other data Locus Chr. 19 q13.2-q13.4 Search for Structures Swiss-model Domains InterPro

HNF4

Members of the HNF4 subfamily are nuclear receptors and bind to DNA either as homodimers or RXR heterodimers.

• HNF4α/TCF14/MODY1
• HNF4γ

hepatocyte nuclear factor 4 alpha Identifiers Symbol HNF4A Alt. symbols MODY, MODY1, NR2A1, TCF14 NCBI gene 3172 HGNC 5024 OMIM 600281 PDB 1M7W RefSeq NM_001030004 UniProt P41235 Other data Locus Chr. 20 q12-20q13.1 Search for Structures Swiss-model Domains InterPro

hepatocyte nuclear factor 4 gamma Identifiers Symbol HNF4G Alt. symbols NR2A2 NCBI gene 3174 HGNC 5026 OMIM 605966 PDB 1LV2 RefSeq NM_004133 UniProt Q14541 Other data Locus Chr. 8 q21-q22 Search for Structures Swiss-model Domains InterPro

HNF6

The HNF6 subfamily members contain a cut-homeodomain (ONECUT) bind to DNA as monomers.

• HNF6α/OC-1/ONECUT1 ( ONECUT1 )
• HNF6β/OC-2/ONECUT2 ( ONECUT2 )

hepatocyte nuclear factor 6, alpha Identifiers Symbol ONECUT1 Alt. symbols HNF6, HNF6A NCBI gene 3175 HGNC 8138 OMIM 604164 RefSeq NM_004498 UniProt Q9UBC0 Other data Locus Chr. 15 q21-q21.2 Search for Structures Swiss-model Domains InterPro

hepatocyte nuclear factor 6, beta Identifiers Symbol ONECUT2 Alt. symbols HNF6B, OC-2 NCBI gene 9480 HGNC 8139 OMIM 604894 RefSeq NM_004852 UniProt O95948 Other data Locus Chr. 18 q21.1-21.2 Search for Structures Swiss-model Domains InterPro

See also

• HNF4
• Transcription (genetics)
• Maturity onset diabetes of the young

References

1. Costa RH, Kalinichenko VV, Holterman AX, Wang X (2003). "Transcription factors in liver development, differentiation, and regeneration". Hepatology. 38 (6): 1331–47. doi: 10.1016/j.hep.2003.09.034 . PMID   14647040. S2CID   2646966.
2. Mitchell SM, Frayling TM (2002). "The role of transcription factors in maturity-onset diabetes of the young". Mol Genet Metab. 77 (1–2): 35–43. doi:10.1016/S1096-7192(02)00150-6. PMID   12359128.
3. Ryffel GU (2001). "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. doi: 10.1677/jme.0.0270011 . PMID   11463573.

Additional images

• 
  Hepatocyte nuclear factor 1A bound to DNA
• 
  Different rendering of HNF1a bound to DNA

External links

• Hepatocyte+Nuclear+Factors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Transcription networks in the liver
• transthyretin promoter, an example of a regulatory region containing HNF binding sites
• HNF4 in genetics of diabetes