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.

Structure

FOXA2 belongs to a subfamily of the

Forkhead box FOX (forkhead box) proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. Many FOX proteins are important to embryonic ...

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

Functions

FOXA transcription factors have “ pioneering” property, i.e. they can directly bind to condensed chromatin. This feature has been observed both ''in vitro'' and ''in vivo'', where FOXA transcription factors can bind nucleosome-bound target DNA sequences. The pioneering property is conferred by the factors’ highly conserved DNA-binding domain, which is structurally similar to the linker histones H1 and H5 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. Thus, FOXA2 have important roles in cell type specification by promoting chromatin accessibility for the binding of lineage- or tissue-specific factors 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. One example is that ectopic expression of FOXA2 together with

HNF4A Hepatocyte nuclear factor 4 alpha (HNF4A) also known as NR2A1 (nuclear receptor subfamily 2, group A, member 1) is a nuclear receptor that in humans is encoded by the ''HNF4A'' gene. Function HNF-4α is a nuclear transcription factor that bi ...

drives transdifferentiation of fibroblasts to hepatocyte-like cells.
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 The primitive streak is a structure that forms in the early embryo in amniotes. In amphibians, the equivalent structure is the blastopore. During early embryonic development, the embryonic disc becomes oval shaped, and then pear-shaped with the ...

and

node In general, a node is a localized swelling (a "knot") or a point of intersection (a vertex). Node may refer to: In mathematics * Vertex (graph theory), a vertex in a mathematical graph *Vertex (geometry), a point where two or more curves, lines ...

at embryonic day (E) 6.5, and in the mesoderm and definitive

endoderm Endoderm is the innermost of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer). Cells migrating inward along the archenteron form the inner layer of the gastr ...

at E7.5. Its expression is subsequently maintained in endoderm-derived tissues, including the pancreas, liver, prostate, thyroid and lung, throughout development and in mature tissues. In addition, Foxa2 is expressed in

ectoderm The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm (the middle layer) and endoderm (the innermost layer). It emerges and originates from the o ...

-derived neural tissues. ''Foxa2''

knockout A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, Muay Thai, mixed martial arts, karate, some forms of taekwondo and other sports involving striking, ...

is embryonically lethal to mice, which die between E10 and E11 and show defects in all three germ layers. Mice with heterozygosity for ''Foxa2'' knockout are viable and exhibit a phenotype similar to Parkinson's disease upon aging. 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. 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. 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

References

External links

* {{Transcription factors, g3 Forkhead transcription factors