{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nATF7 is a stress‐responsive transcription factor that mediates key epigenetic changes in germ cells, linking paternal environmental stressors to gene regulation in offspring. In mouse testicular germ cells, ATF7 binds to promoters of thousands of genes, including those involved in cholesterol biosynthesis and tRNA production, and under conditions such as a low‐protein diet, phosphorylation of ATF7 via p38 signaling leads to its release and a subsequent reduction of histone H3K9 dimethylation. These epigenetic modifications are subsequently maintained in spermatozoa, thereby contributing to metabolic reprogramming and even telomere dynamics, as stress‐induced phosphorylation of ATF7 both in subtelomeric regions and on telomeres leads to TERRA induction and telomere shortening that can be transmitted to the next generation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the central nervous system and in metabolic tissues, ATF7 functions as a critical transcriptional repressor and regulator of tissue homeostasis. In the dorsal raphe nuclei, for instance, ATF7 binds to the regulatory region of the 5‑HT receptor Htr5b, maintaining its transcriptional silencing under nonstressed conditions, whereas social isolation induces p38-mediated phosphorylation of ATF7, releasing it from chromatin and thereby upregulating Htr5b expression—a mechanism that may underlie behavioural abnormalities. Similarly, in adipose tissue, genetic ablation of ATF7 is associated with reduced adipose mass, increased energy expenditure under high-fat conditions, and overall resistance to diet-induced obesity, while its redundant roles with ATF2 have also been explored in maintaining intestinal epithelial homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nATF7 further participates in cell fate decisions across diverse systems through its interaction with co-activators and epigenetic enzymes. In osteoclast precursors, ATF7 physically interacts with TAF12—a coactivator of the vitamin D receptor—facilitating hypersensitivity to calcitriol and contributing to the pathological features of Paget’s disease. In the cardiovascular system, a specific piRNA (HNEAP) modulates m5C methylation on the ATF7 mRNA by interfering with DNMT1, leading to elevated ATF7 levels that downregulate CHMP2A, thereby promoting cardiomyocyte necroptosis in ischemia/reperfusion injury. Additionally, in the context of cellular aging, ATF7 binds the promoter of the Cdk inhibitor p16Ink4a and normally recruits histone methyltransferases to establish repressive marks; age-associated p38-dependent phosphorylation of ATF7 results in its release and a concomitant rise in p16Ink4a expression, thus contributing to premature senescence."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Keisuke Yoshida, Toshio Maekawa, Nhung Hong Ly, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Telomere shortening by transgenerational transmission of TNF-α-induced TERRA via ATF7."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gky1149"}], "href": "https://doi.org/10.1093/nar/gky1149"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30407559"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30407559"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Toshio Maekawa, Binbin Liu, Daisuke Nakai, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Social isolation stress induces ATF-7 phosphorylation and impairs silencing of the 5-HT 5B receptor gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2009.318"}], "href": "https://doi.org/10.1038/emboj.2009.318"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19893493"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19893493"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Yang Liu, Toshio Maekawa, Keisuke Yoshida, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ATF7 ablation prevents diet-induced obesity and insulin resistance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2016.08.009"}], "href": "https://doi.org/10.1016/j.bbrc.2016.08.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27498002"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27498002"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Bartolomeus J Meijer, Francesca P Giugliano, Bart Baan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ATF2 and ATF7 Are Critical Mediators of Intestinal Epithelial Repair."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Gastroenterol Hepatol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jcmgh.2020.01.005"}], "href": "https://doi.org/10.1016/j.jcmgh.2020.01.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31958521"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31958521"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Jumpei Teramachi, Yuko Hiruma, Seiichi Ishizuka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of ATF7-TAF12 interactions in the vitamin D response hypersensitivity of osteoclast precursors in Paget's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Bone Miner Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jbmr.1884"}], "href": "https://doi.org/10.1002/jbmr.1884"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23426901"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23426901"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Kai Wang, Fu-Hai Li, Lu-Yu Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HNEAP Regulates Necroptosis of Cardiomyocytes by Suppressing the m"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "5"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " C Methylation of Atf7 mRNA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Adv Sci (Weinh) (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/advs.202304329"}], "href": "https://doi.org/10.1002/advs.202304329"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37870216"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37870216"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Toshio Maekawa, Binbin Liu, Yang Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Stress-induced and ATF7-dependent epigenetic change influences cellular senescence."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Cells (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/gtc.12713"}], "href": "https://doi.org/10.1111/gtc.12713"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31294895"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31294895"}]}]}]}