{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nASH2L is a core subunit of the COMPASS histone methyltransferase complex that catalyzes H3K4 methylation, a key epigenetic mark associated with active chromatin and transcriptional activation. It functions as a transcriptional co‐activator by interacting with various DNA binding proteins – for example, Tbx1 in cardiac progenitors"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ", Ap2δ in gene‐specific recruitment"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", and the non‐coding RNA Xist."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In embryonic stem cells, ASH2L is critical for maintaining open chromatin states and pluripotency, working in tandem with factors such as Oct4"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "and through binding to super‐enhancers of core stemness genes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Moreover, its deletion in mouse embryonic fibroblasts results in global reduction of H3K4 trimethylation and drives a senescence phenotype."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "2"}, {"type": "fg_fs", "start_ref": "4", "end_ref": "6"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond maintaining pluripotency, ASH2L orchestrates lineage‐ and tissue-specific gene expression programs during development. Its role is demonstrated in neural tissues where it is essential for neocortical development and proper neural progenitor cell proliferation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", in the hematopoietic system where it is required for balanced cell cycle progression and differentiation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and in epithelial lineages affecting both dental amelogenesis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "and epidermal/hair follicle morphogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In addition, in breast epithelial cells ASH2L enhances estrogen receptor‐α transcription via its interaction with GATA3"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", underscoring its broad impact in developmental and tissue‐specific contexts."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}, {"type": "fg_f", "ref": "11"}, {"type": "fg_f", "ref": "9"}, {"type": "fg_f", "ref": "12"}, {"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nASH2L also has pivotal roles in pathological contexts. 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"}, {"type": "b", "children": [{"type": "t", "text": "Xist RNA repeat E is essential for ASH2L recruitment to the inactive X and regulates histone modifications and escape gene expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1006890"}], "href": "https://doi.org/10.1371/journal.pgen.1006890"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28686623"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28686623"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Shuang Li, Feng Xiao, Junmei Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Disruption of OCT4 Ubiquitination Increases OCT4 Protein Stability and ASH2L-B-Mediated H3K4 Methylation Promoting Pluripotency Acquisition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cell Reports (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.stemcr.2018.09.001"}], "href": "https://doi.org/10.1016/j.stemcr.2018.09.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30269953"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30269953"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ping-Hsing Tsai, Yueh Chien, Mong-Lien Wang, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Loss of the Ash2l subunit of histone H3K4 methyltransferase complexes reduces chromatin accessibility at promoters."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-022-25881-0"}], "href": "https://doi.org/10.1038/s41598-022-25881-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36513698"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36513698"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Ma Wan, Jiancong Liang, Yuanyan Xiong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The trithorax group protein Ash2l is essential for pluripotency and maintaining open chromatin in embryonic stem cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.424515"}], "href": "https://doi.org/10.1074/jbc.M112.424515"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23239880"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23239880"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Liang Li, Xiangbin Ruan, Chang Wen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The COMPASS Family Protein ASH2L Mediates Corticogenesis via Transcriptional Regulation of Wnt Signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2019.06.055"}], "href": "https://doi.org/10.1016/j.celrep.2019.06.055"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31315048"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31315048"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Ya-Jie Xu, Shang-Kun Dai, Chun-Hui Duan, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Hematopoietic stem and progenitor cell proliferation and differentiation requires the trithorax protein Ash2l."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-019-44720-3"}], "href": "https://doi.org/10.1038/s41598-019-44720-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31164666"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31164666"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "X Zhu, Z Ma, F Xie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ASH2L, Core Subunit of H3K4 Methylation Complex, Regulates Amelogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Dent Res (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/00220345231207309"}], "href": "https://doi.org/10.1177/00220345231207309"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37990471"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37990471"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Qirui Wang, Siyi Zeng, Yimin Liang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ASH2L Mediates Epidermal Differentiation and Hair Follicle Morphogenesis through H3K4me3 Modification."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Invest Dermatol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jid.2024.03.035"}], "href": "https://doi.org/10.1016/j.jid.2024.03.035"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38582368"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38582368"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Jin Qi, Lei Huo, Yiwei Tony Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Absent, small or homeotic 2-like protein (ASH2L) enhances the transcription of the estrogen receptor α gene through GATA-binding protein 3 (GATA3)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M114.579839"}], "href": "https://doi.org/10.1074/jbc.M114.579839"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25258321"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25258321"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Wen Zhong, Chen Hong, Yejun Dong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ASH2L Aggravates Fibrosis and Inflammation through HIPK2 in High Glucose-Induced Glomerular Mesangial Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes (Basel) (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/genes13122244"}], "href": "https://doi.org/10.3390/genes13122244"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36553510"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36553510"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Wen Zhong, Chen Hong, Yuyu Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ASH2L-mediated H3K4me3 drives diabetic nephropathy through HIPK2 and Notch1 pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Transl Res (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.trsl.2023.10.002"}], "href": "https://doi.org/10.1016/j.trsl.2023.10.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37879562"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37879562"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Zhenghua Su, Jinghuan Wang, Chenxi Xiao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional role of Ash2l in oxLDL induced endothelial dysfunction and atherosclerosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Life Sci (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00018-024-05130-5"}], "href": "https://doi.org/10.1007/s00018-024-05130-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38280036"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38280036"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Mengjie Ma, Jiafeng Zhou, Zhihua Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Ash2l SDI Domain Is Required to Maintain the Stability and Binding of DPY30."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cells (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/cells11091450"}], "href": "https://doi.org/10.3390/cells11091450"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35563756"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35563756"}]}]}]}