{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nARNT2 is a member of the basic helix-loop-helix/Per-Arnt-Sim (bHLH-PAS) transcription factor family that plays a pivotal role in tissue-specific transcriptional responses. In developing kidney, for example, ARNT2 (also known as HIF‑2β) is expressed at high levels in distal nephron segments and in the thick ascending limb of Henle, where it partners with HIF‐α subunits to regulate cellular responses to oxygen deprivation. Notably, its expression pattern differs markedly from the ubiquitous HIF‑1β, indicating a specialized role in nephrogenesis and oxygen homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the central nervous system, ARNT2 is a key regulator of neuronal gene expression and circuit function. In the mouse hippocampus, deep sequencing analysis of transcription start sites has revealed that ARNT2 contributes to the regulation of novel core promoters, suggesting its integral role in tuning transcription. Its function extends to activity‐dependent neuronal programs: in the absence of synaptic excitation, ARNT2 recruits a co‐repressor complex to suppress basal levels of inducible genes, while during heightened synaptic activity it partners with neuronal-specific factors such as NPAS4 to induce transcription that scales inhibitory input. Moreover, selective disruption of ARNT2 expression in anterior cingulate somatostatin interneurons impairs affect sharing and observational fear—key components of empathy—thereby linking ARNT2 to social affective behaviors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in development and neuronal plasticity, ARNT2 is important for maintaining systemic homeostasis. Studies comparing its dimerization capabilities have revealed that, unlike its homolog ARNT, ARNT2 shows differential interactions with ligand-activated receptors to regulate the expression of xenobiotic-metabolizing enzymes. In addition, mutation of ARNT2—specifically a missense change (Arg74Cys)—leads to hyperphagia, increased adiposity, hepatic steatosis, and impaired glucose homeostasis, underscoring its involvement in metabolic regulation. ARNT2 has also been implicated in neuroprotective responses, as its expression is associated with reductions in axonal degeneration and neuronal loss in disease models."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Paul B Freeburg, Dale R Abrahamson "}, {"type": "b", "children": [{"type": "t", "text": "Divergent expression patterns for hypoxia-inducible factor-1beta and aryl hydrocarbon receptor nuclear transporter-2 in developing kidney."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Am Soc Nephrol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/01.ASN.0000141464.02967.29"}], "href": "https://doi.org/10.1097/01.ASN.0000141464.02967.29"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15466261"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15466261"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Hiroki Sekine, Junsei Mimura, Masayuki Yamamoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Unique and overlapping transcriptional roles of arylhydrocarbon receptor nuclear translocator (Arnt) and Arnt2 in xenobiotic and hypoxic responses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M606910200"}], "href": "https://doi.org/10.1074/jbc.M606910200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17023418"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17023418"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Eivind Valen, Giovanni Pascarella, Alistair Chalk, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-wide detection and analysis of hippocampus core promoters using DeepCAGE."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genome Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gr.084541.108"}], "href": "https://doi.org/10.1101/gr.084541.108"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19074369"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19074369"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Nikhil Sharma, Elizabeth A Pollina, M Aurel Nagy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ARNT2 Tunes Activity-Dependent Gene Expression through NCoR2-Mediated Repression and NPAS4-Mediated Activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuron (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuron.2019.02.007"}], "href": "https://doi.org/10.1016/j.neuron.2019.02.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30846309"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30846309"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Jiye Choi, Seungmoon Jung, Jieun Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ARNT2 controls prefrontal somatostatin interneurons mediating affective empathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2024.114659"}], "href": "https://doi.org/10.1016/j.celrep.2024.114659"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39180750"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39180750"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Tissa Rahim, Pierre Becquart, Maria-Elizabeth Baeva, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of the neuroprotective protein aryl hydrocarbon receptor nuclear translocator 2 correlates with neuronal stress and disability in models of multiple sclerosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neuroinflammation (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12974-018-1290-6"}], "href": "https://doi.org/10.1186/s12974-018-1290-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30231889"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30231889"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Emre E Turer, Miguel San Miguel, Kuan-Wen Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A viable hypomorphic "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "Arnt2"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " mutation causes hyperphagic obesity, diabetes and hepatic steatosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dis Model Mech (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dmm.035451"}], "href": "https://doi.org/10.1242/dmm.035451"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30563851"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30563851"}]}]}]}