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FOXA2

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FOXA2
Identifiers
AliasesFOXA2, HNF3B, TCF3B, forkhead box A2, HNF-3-beta
External IDsOMIM: 600288; MGI: 1347476; HomoloGene: 7762; GeneCards: FOXA2; OMA:FOXA2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3170

15376

Ensembl

ENSG00000125798

ENSMUSG00000037025

UniProt

Q9Y261

P35583

RefSeq (mRNA)

NM_021784
NM_153675

NM_001291065
NM_001291067
NM_010446

RefSeq (protein)

NP_068556
NP_710141

NP_001277994
NP_001277996
NP_034576

Location (UCSC)Chr 20: 22.58 – 22.59 MbChr 2: 147.88 – 147.89 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Forkhead box protein A2 (FOXA2), also known as hepatocyte nuclear factor 3-beta (HNF-3B), is a transcription factor that plays an important role during development, in mature tissues and, when dysregulated or mutated, also in cancer.[5]

Structure

FOXA2 belongs to a subfamily of the Forkhead box (FOX) transcription factors, the other members being FOXA1 and FOXA3. This subfamily of mammalian FOX proteins was first identified because of their ability to bind DNA in rat liver nuclear extracts. The proteins were therefore originally named hepatocyte nuclear factor 3 alpha, beta and gamma.[6] These transcription factors contain a forkhead domain (also known as the winged-helix domain) flanked by sequences necessary for nuclear localization [7] Their N- and C-termini are also conserved and serve as transactivation domains.[8][9]

Functions

FOXA transcription factors have “pioneering” property, i.e. they can directly bind to condensed chromatin.[5] This feature has been observed both in vitro and in vivo, where FOXA transcription factors can bind nucleosome-bound target DNA sequences.[10][11] The pioneering property is conferred by the factors’ highly conserved DNA-binding domain, which is structurally similar to the linker histones H1 and H5 [12][13] This feature enables FOXA2 to access closed chromatin and displace linker histones. In this way, FOXA2 promotes local chromatin opening, permits the recruitment of alternative histones and facilitates the subsequent binding of other transcription factors.[10][14][15] Thus, FOXA2 have important roles in cell type specification by promoting chromatin accessibility for the binding of lineage- or tissue-specific factors [16] The FOXA factors also facilitate the maintenance of cell identity by bookmarking cell type-specific genes so that these genes can be rapidly reactivated after cytokinesis.[17] One example is that ectopic expression of FOXA2 together with HNF4A drives transdifferentiation of fibroblasts to hepatocyte-like cells.[18]


Consistent with its role as a pioneering transcription factor, FOXA2 is expressed in early development and essential for the development and homeostasis of various cell types and tissues. In mice, Foxa2 expression emerges in the primitive streak and node at embryonic day (E) 6.5, and in the mesoderm and definitive endoderm at E7.5.[19][20] Its expression is subsequently maintained in endoderm-derived tissues, including the pancreas, liver, prostate, thyroid and lung, throughout development and in mature tissues.[7] In addition, Foxa2 is expressed in ectoderm-derived neural tissues.[21] Foxa2 knockout is embryonically lethal to mice, which die between E10 and E11 and show defects in all three germ layers.[22][23] Mice with heterozygosity for Foxa2 knockout are viable and exhibit a phenotype similar to Parkinson’s disease upon aging.[24] Conditional knockout studies show that Foxa2 is important for the formation of pancreatic islets and maturation of alpha and beta cells, thereby being essential for glucose homeostasis.[25][26]

Dysregulation of FOXA transcription factors have been linked to several types of human cancers, including acute myeloid leukemia and cancer of the esophagus, lung, thyroid, pancreas, breast and prostate.[27] Single nucleotide polymorphisms in the FOXA2 gene are associated with hepatocellular carcinoma, especially in males. This association has been replicated in mice and may depend on androgen receptor-mediated regulation [28]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000125798 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000037025 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b Golson ML, Kaestner KH (December 2016). "Fox transcription factors: from development to disease". Development. 143 (24): 4558–4570. doi:10.1242/dev.112672. PMC 5201025. PMID 27965437.
  6. ^ Costa RH, Grayson DR, Darnell JE (April 1989). "Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes". Molecular and Cellular Biology. 9 (4): 1415–25. doi:10.1128/mcb.9.4.1415. PMC 362558. PMID 2786140.
  7. ^ a b Friedman JR, Kaestner KH (October 2006). "The Foxa family of transcription factors in development and metabolism". Cellular and Molecular Life Sciences. 63 (19–20): 2317–28. doi:10.1007/s00018-006-6095-6. PMID 16909212. S2CID 12385486.
  8. ^ Pani L, Quian XB, Clevidence D, Costa RH (February 1992). "The restricted promoter activity of the liver transcription factor hepatocyte nuclear factor 3 beta involves a cell-specific factor and positive autoactivation". Molecular and Cellular Biology. 12 (2): 552–62. doi:10.1128/mcb.12.2.552. PMC 364229. PMID 1732730.
  9. ^ Qian X, Costa RH (April 1995). "Analysis of hepatocyte nuclear factor-3 beta protein domains required for transcriptional activation and nuclear targeting". Nucleic Acids Research. 23 (7): 1184–91. doi:10.1093/nar/23.7.1184. PMC 306829. PMID 7739897.
  10. ^ a b Cirillo LA, Lin FR, Cuesta I, Friedman D, Jarnik M, Zaret KS (February 2002). "Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4". Molecular Cell. 9 (2): 279–89. doi:10.1016/s1097-2765(02)00459-8. PMID 11864602.
  11. ^ Cirillo LA, Zaret KS (December 1999). "An early developmental transcription factor complex that is more stable on nucleosome core particles than on free DNA". Molecular Cell. 4 (6): 961–9. doi:10.1016/s1097-2765(00)80225-7. PMID 10635321.
  12. ^ Clark KL, Halay ED, Lai E, Burley SK (July 1993). "Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5". Nature. 364 (6436): 412–20. Bibcode:1993Natur.364..412C. doi:10.1038/364412a0. PMID 8332212. S2CID 4363526.
  13. ^ Zaret KS, Caravaca JM, Tulin A, Sekiya T (2010). "Nuclear mobility and mitotic chromosome binding: similarities between pioneer transcription factor FoxA and linker histone H1". Cold Spring Harbor Symposia on Quantitative Biology. 75: 219–26. doi:10.1101/sqb.2010.75.061. PMID 21502411.
  14. ^ Li Z, Gadue P, Chen K, Jiao Y, Tuteja G, Schug J, et al. (December 2012). "Foxa2 and H2A.Z mediate nucleosome depletion during embryonic stem cell differentiation". Cell. 151 (7): 1608–16. doi:10.1016/j.cell.2012.11.018. PMC 3530164. PMID 23260146.
  15. ^ Updike DL, Mango SE (September 2006). "Temporal regulation of foregut development by HTZ-1/H2A.Z and PHA-4/FoxA". PLOS Genetics. 2 (9): e161. doi:10.1371/journal.pgen.0020161. PMC 1584275. PMID 17009877.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  16. ^ Iwafuchi-Doi M, Zaret KS (June 2016). "Cell fate control by pioneer transcription factors". Development. 143 (11): 1833–7. doi:10.1242/dev.133900. PMC 6514407. PMID 27246709.
  17. ^ Caravaca JM, Donahue G, Becker JS, He X, Vinson C, Zaret KS (February 2013). "Bookmarking by specific and nonspecific binding of FoxA1 pioneer factor to mitotic chromosomes". Genes & Development. 27 (3): 251–60. doi:10.1101/gad.206458.112. PMC 3576511. PMID 23355396.
  18. ^ Sekiya S, Suzuki A (June 2011). "Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors". Nature. 475 (7356): 390–3. doi:10.1038/nature10263. PMID 21716291. S2CID 205225695.
  19. ^ Monaghan AP, Kaestner KH, Grau E, Schütz G (November 1993). "Postimplantation expression patterns indicate a role for the mouse forkhead/HNF-3 alpha, beta and gamma genes in determination of the definitive endoderm, chordamesoderm and neuroectoderm". Development. 119 (3): 567–78. doi:10.1242/dev.119.3.567. PMID 8187630.
  20. ^ Ang SL, Wierda A, Wong D, Stevens KA, Cascio S, Rossant J, Zaret KS (December 1993). "The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF3/forkhead proteins". Development. 119 (4): 1301–15. doi:10.1242/dev.119.4.1301. PMID 8306889.
  21. ^ Besnard V, Wert SE, Hull WM, Whitsett JA (December 2004). "Immunohistochemical localization of Foxa1 and Foxa2 in mouse embryos and adult tissues". Gene Expression Patterns. 5 (2): 193–208. doi:10.1016/j.modgep.2004.08.006. PMID 15567715.
  22. ^ Weinstein DC, Ruiz i Altaba A, Chen WS, Hoodless P, Prezioso VR, Jessell TM, Darnell JE (August 1994). "The winged-helix transcription factor HNF-3 beta is required for notochord development in the mouse embryo". Cell. 78 (4): 575–88. doi:10.1016/0092-8674(94)90523-1. PMID 8069910. S2CID 21650241.
  23. ^ Ang SL, Rossant J (August 1994). "HNF-3 beta is essential for node and notochord formation in mouse development". Cell. 78 (4): 561–74. doi:10.1016/0092-8674(94)90522-3. PMID 8069909. S2CID 54291913.
  24. ^ Kittappa R, Chang WW, Awatramani RB, McKay RD (December 2007). "The foxa2 gene controls the birth and spontaneous degeneration of dopamine neurons in old age". PLOS Biology. 5 (12): e325. doi:10.1371/journal.pbio.0050325. PMC 2121110. PMID 18076286.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  25. ^ Sund NJ, Ang SL, Sackett SD, Shen W, Daigle N, Magnuson MA, Kaestner KH (July 2000). "Hepatocyte nuclear factor 3beta (Foxa2) is dispensable for maintaining the differentiated state of the adult hepatocyte". Molecular and Cellular Biology. 20 (14): 5175–83. doi:10.1128/mcb.20.14.5175-5183.2000. PMC 85966. PMID 10866673.
  26. ^ Lantz KA, Vatamaniuk MZ, Brestelli JE, Friedman JR, Matschinsky FM, Kaestner KH (August 2004). "Foxa2 regulates multiple pathways of insulin secretion". The Journal of Clinical Investigation. 114 (4): 512–20. doi:10.1172/JCI21149. PMC 503770. PMID 15314688.
  27. ^ Lau HH, Ng NH, Loo LS, Jasmen JB, Teo AK (May 2018). "The molecular functions of hepatocyte nuclear factors - In and beyond the liver". Journal of Hepatology. 68 (5): 1033–1048. doi:10.1016/j.jhep.2017.11.026. PMID 29175243.
  28. ^ Li Z, Tuteja G, Schug J, Kaestner KH (January 2012). "Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer". Cell. 148 (1–2): 72–83. doi:10.1016/j.cell.2011.11.026. PMC 3266536. PMID 22265403.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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