HNF3

Hepatocyte Nuclear Factor 3 (HNF3) is a family of transcription factors in vertebrates belonging to the forkhead box (FOX) family. The three paralogs originally described as HNF3A, HNF3B, and HNF3G are now commonly referred to as FOXA1, FOXA2, and FOXA3, respectively. The legacy name HNF3 is still encountered in some literature, but the FOXA nomenclature is standard in contemporary discussions.

HNF3/FOXA proteins share a conserved forkhead (winged-helix) DNA-binding domain and function as pioneer transcription factors. They can bind to compact chromatin and facilitate the access of other transcription factors, thereby helping to establish gene regulatory networks. In addition to binding to promoters and enhancers, FOXA factors interact with other regulators to control gene expression programs.

Expression of FOXA1-3 is enriched in endoderm-derived tissues, including the liver, pancreas, intestine, and lungs, with distinct but overlapping patterns during development. FOXA2, in particular, is essential for primitive endoderm formation and for hepatic and pancreatic organogenesis; loss of function in model systems results in severe developmental defects. FOXA1 and FOXA3 contribute to similar regulatory networks and can compensate in part for each other in certain contexts.

In adults, FOXA factors help maintain liver-specific gene expression and influence metabolic gene regulation. Dysregulation of FOXA factors has been implicated in various diseases, including liver and pancreatic cancers and metabolic disorders. Today, HNF3 is primarily discussed under the FOXA1/FOXA2/FOXA3 terminology, reflecting its role in development and organogenesis as a pioneer transcription factor.