{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n FOXA2, a pioneer member of the forkhead transcription factor family, plays multifaceted roles in embryonic development and adult tissue homeostasis by orchestrating distinct gene networks across multiple organ systems. In early liver development, FOXA2—working in concert with FOXA1—facilitates chromatin opening to establish foregut endoderm competence and drive hepatic specification and liver bud formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the adult liver, FOXA2 is pivotal for metabolic homeostasis; its nuclear localization during fasting activates transcriptional programs that promote lipid metabolism, ketogenesis, and gluconeogenesis, while its dysregulation contributes to metabolic disorders such as nonalcoholic fatty liver disease and type 2 diabetes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "5"}]}, {"type": "t", "text": " In pancreatic development, FOXA2 collaborates with FOXA1 to regulate key genes such as Pdx1, ensuring the proper expansion and differentiation of pancreatic progenitors; moreover, in pancreatic ductal adenocarcinoma, retention of FOXA2 expression antagonizes epithelial-to-mesenchymal transition by upregulating E-cadherin, thereby maintaining an epithelial phenotype."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Further, in pulmonary morphogenesis, FOXA2 (together with FOXA1) regulates key signaling pathways, including sonic hedgehog, to direct proper branching of the respiratory epithelium."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In the developing midbrain, FOXA2 is essential for the specification and differentiation of dopaminergic neurons by modulating the expression of genes such as Ngn2 and Nurr1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Finally, FOXA2 also contributes to cardiac and craniofacial ontogeny by participating in the regulation of Tbx1 transcription via conserved forkhead‐binding elements, underscoring its broader role in tissue patterning."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings highlight FOXA2 as a master regulator that integrates developmental signals and metabolic cues to modulate gene expression programs critical for organ specification, function, and disease susceptibility.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Catherine S Lee, Joshua R Friedman, James T Fulmer, et al. 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