Biology:FOXA2

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1]

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.[2] These transcription factors contain a forkhead domain (also known as the winged-helix domain) flanked by sequences necessary for nuclear localization [3] Their N- and C-termini are also conserved and serve as transactivation domains.[4][5]

Functions

FOXA transcription factors have “pioneering” property, i.e. they can directly bind to condensed chromatin.[1] This feature has been observed both in vitro and in vivo, where FOXA transcription factors can bind nucleosome-bound target DNA sequences.[6][7] The pioneering property is conferred by the factors’ highly conserved DNA-binding domain, which is structurally similar to the linker histones H1 and H5 [8][9] 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.[6][10][11] Thus, FOXA2 have important roles in cell type specification by promoting chromatin accessibility for the binding of lineage- or tissue-specific factors [12] 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.[13] One example is that ectopic expression of FOXA2 together with HNF4A drives transdifferentiation of fibroblasts to hepatocyte-like cells.[14]


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.[15][16] Its expression is subsequently maintained in endoderm-derived tissues, including the pancreas, liver, prostate, thyroid and lung, throughout development and in mature tissues.[3] In addition, Foxa2 is expressed in ectoderm-derived neural tissues.[17] Foxa2 knockout is embryonically lethal to mice, which die between E10 and E11 and show defects in all three germ layers.[18][19] Mice with heterozygosity for Foxa2 knockout are viable and exhibit a phenotype similar to Parkinson's disease upon aging.[20] 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.[21][22]

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.[23] 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 [24]

References

  1. ↑ 1.0 1.1 "Fox transcription factors: from development to disease". Development 143 (24): 4558–4570. December 2016. doi:10.1242/dev.112672. PMID 27965437. 
  2. ↑ "Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes". Molecular and Cellular Biology 9 (4): 1415–25. April 1989. doi:10.1128/mcb.9.4.1415. PMID 2786140. 
  3. ↑ 3.0 3.1 "The Foxa family of transcription factors in development and metabolism". Cellular and Molecular Life Sciences 63 (19–20): 2317–28. October 2006. doi:10.1007/s00018-006-6095-6. PMID 16909212. 
  4. ↑ "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. February 1992. doi:10.1128/mcb.12.2.552. PMID 1732730. 
  5. ↑ "Analysis of hepatocyte nuclear factor-3 beta protein domains required for transcriptional activation and nuclear targeting". Nucleic Acids Research 23 (7): 1184–91. April 1995. doi:10.1093/nar/23.7.1184. PMID 7739897. 
  6. ↑ 6.0 6.1 "Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4". Molecular Cell 9 (2): 279–89. February 2002. doi:10.1016/s1097-2765(02)00459-8. PMID 11864602. 
  7. ↑ "An early developmental transcription factor complex that is more stable on nucleosome core particles than on free DNA". Molecular Cell 4 (6): 961–9. December 1999. doi:10.1016/s1097-2765(00)80225-7. PMID 10635321. 
  8. ↑ "Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5". Nature 364 (6436): 412–20. July 1993. doi:10.1038/364412a0. PMID 8332212. Bibcode: 1993Natur.364..412C. 
  9. ↑ "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. 2010. doi:10.1101/sqb.2010.75.061. PMID 21502411. 
  10. ↑ "Foxa2 and H2A.Z mediate nucleosome depletion during embryonic stem cell differentiation". Cell 151 (7): 1608–16. December 2012. doi:10.1016/j.cell.2012.11.018. PMID 23260146. 
  11. ↑ "Temporal regulation of foregut development by HTZ-1/H2A.Z and PHA-4/FoxA". PLOS Genetics 2 (9): e161. September 2006. doi:10.1371/journal.pgen.0020161. PMID 17009877. 
  12. ↑ "Cell fate control by pioneer transcription factors". Development 143 (11): 1833–7. June 2016. doi:10.1242/dev.133900. PMID 27246709. 
  13. ↑ "Bookmarking by specific and nonspecific binding of FoxA1 pioneer factor to mitotic chromosomes". Genes & Development 27 (3): 251–60. February 2013. doi:10.1101/gad.206458.112. PMID 23355396. 
  14. ↑ "Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors". Nature 475 (7356): 390–3. June 2011. doi:10.1038/nature10263. PMID 21716291. 
  15. ↑ "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. November 1993. doi:10.1242/dev.119.3.567. PMID 8187630. 
  16. ↑ "The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF3/forkhead proteins". Development 119 (4): 1301–15. December 1993. doi:10.1242/dev.119.4.1301. PMID 8306889. 
  17. ↑ "Immunohistochemical localization of Foxa1 and Foxa2 in mouse embryos and adult tissues". Gene Expression Patterns 5 (2): 193–208. December 2004. doi:10.1016/j.modgep.2004.08.006. PMID 15567715. 
  18. ↑ "The winged-helix transcription factor HNF-3 beta is required for notochord development in the mouse embryo". Cell 78 (4): 575–88. August 1994. doi:10.1016/0092-8674(94)90523-1. PMID 8069910. 
  19. ↑ "HNF-3 beta is essential for node and notochord formation in mouse development". Cell 78 (4): 561–74. August 1994. doi:10.1016/0092-8674(94)90522-3. PMID 8069909. 
  20. ↑ "The foxa2 gene controls the birth and spontaneous degeneration of dopamine neurons in old age". PLOS Biology 5 (12): e325. December 2007. doi:10.1371/journal.pbio.0050325. PMID 18076286. 
  21. ↑ "Hepatocyte nuclear factor 3beta (Foxa2) is dispensable for maintaining the differentiated state of the adult hepatocyte". Molecular and Cellular Biology 20 (14): 5175–83. July 2000. doi:10.1128/mcb.20.14.5175-5183.2000. PMID 10866673. 
  22. ↑ "Foxa2 regulates multiple pathways of insulin secretion". The Journal of Clinical Investigation 114 (4): 512–20. August 2004. doi:10.1172/JCI21149. PMID 15314688. 
  23. ↑ "The molecular functions of hepatocyte nuclear factors - In and beyond the liver". Journal of Hepatology 68 (5): 1033–1048. May 2018. doi:10.1016/j.jhep.2017.11.026. PMID 29175243. 
  24. ↑ "Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer". Cell 148 (1–2): 72–83. January 2012. doi:10.1016/j.cell.2011.11.026. PMID 22265403. 

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



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