{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HAND2, a basic helix–loop–helix transcription factor, has emerged as a central regulator of multiple developmental processes. In the heart, HAND2 promotes ventricular cardiomyocyte expansion and is essential for proper right ventricular morphogenesis. Its expression is tightly controlled by several mechanisms, including negative regulation by microRNA‐1 that helps balance proliferation and differentiation in cardiac precursors"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ", and by chromatin regulators and upstream transcription factors such as GATA4, with disruption leading to congenital heart defects."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "4"}]}, {"type": "t", "text": " In addition, noncoding RNA transcription is required to maintain a permissive chromatin environment at the HAND2 locus, further underscoring the fine-tuned epigenetic control of its expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond cardiogenesis, HAND2 plays a pivotal role in uterine function; progesterone-induced HAND2 expression in the stromal compartment suppresses multiple fibroblast growth factors, thereby regulating paracrine signaling critical for the attenuation of estrogen-mediated epithelial proliferation and successful implantation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In limb development, a silencer element located downstream of HAND2 mediates Gli3-dependent repression, contributing to the proper polarization of the limb bud."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of craniofacial and neural crest–derived structures, dHAND (a homolog of HAND2) acts as an effector of endothelin‐1 signaling and cooperates with homeodomain proteins to delineate regional identities in the pharyngeal arches."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Moreover, the establishment of mandibular identity requires the coordinated regulation of HAND2 expression, with its loss correlating with shifts in gene networks that distinguish lower jaw structures."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies demonstrate that HAND2 integrates diverse signaling pathways, transcriptional networks, and epigenetic mechanisms to orchestrate organogenesis in a context-dependent manner.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yong Zhao, Eva Samal, Deepak Srivastava "}, {"type": "b", "children": [{"type": "t", "text": "Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature03817"}], "href": "https://doi.org/10.1038/nature03817"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15951802"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15951802"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "David G McFadden, Ana C Barbosa, James A Richardson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Hand1 and Hand2 transcription factors regulate expansion of the embryonic cardiac ventricles in a gene dosage-dependent manner."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Development (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dev.01562"}], "href": "https://doi.org/10.1242/dev.01562"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15576406"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15576406"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Paul D Gottlieb, Stephanie A Pierce, Robert J Sims, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bop encodes a muscle-restricted protein containing MYND and SET domains and is essential for cardiac differentiation and morphogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng866"}], "href": "https://doi.org/10.1038/ng866"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11923873"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11923873"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Elisabeth M Zeisberg, Qing Ma, Amy L Juraszek, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Morphogenesis of the right ventricle requires myocardial expression of Gata4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI23769"}], "href": "https://doi.org/10.1172/JCI23769"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15902305"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15902305"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Kelly M Anderson, Douglas M Anderson, John R McAnally, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcription of the non-coding RNA upperhand controls Hand2 expression and heart development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature20128"}], "href": "https://doi.org/10.1038/nature20128"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27783597"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27783597"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Quanxi Li, Athilakshmi Kannan, Francesco J DeMayo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1197454"}], "href": "https://doi.org/10.1126/science.1197454"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21330545"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21330545"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Steven A Vokes, Hongkai Ji, Wing H Wong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.1693008"}], "href": "https://doi.org/10.1101/gad.1693008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18832070"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18832070"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Beth A Firulli, Dayana Krawchuk, Victoria E Centonze, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Altered Twist1 and Hand2 dimerization is associated with Saethre-Chotzen syndrome and limb abnormalities."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng1525"}], "href": "https://doi.org/10.1038/ng1525"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15735646"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15735646"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "J Charité, D G McFadden, G Merlo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of Dlx6 in regulation of an endothelin-1-dependent, dHAND branchial arch enhancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.931701"}], "href": "https://doi.org/10.1101/gad.931701"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11711438"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11711438"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Louis-Bruno Ruest, Xilin Xiang, Kim-Chew Lim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endothelin-A receptor-dependent and -independent signaling pathways in establishing mandibular identity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Development (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dev.01291"}], "href": "https://doi.org/10.1242/dev.01291"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15306564"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15306564"}]}]}]}