title: Baf60b-mediated ATM-p53 activation blocks cell identity conversion by sensing chromatin opening.
abstract: Lineage conversion by expression of lineage-specific transcription factors is a process of epigenetic remodeling that has low efficiency. The mechanism by which a cell resists lineage conversion is largely unknown. Using hepatic-specific transcription factors Foxa3, Hnf1α and Gata4 (3TF) to induce hepatic conversion in mouse fibroblasts, we showed that 3TF induced strong activation of the ATM-p53 pathway, which led to proliferation arrest and cell death, and it further prevented hepatic conversion. Notably, ATM activation, independent of DNA damage, responded to chromatin opening during hepatic conversion. By characterizing the early molecular events during hepatic conversion, we found that Baf60b, a member of the SWI/SNF chromatin remodeling complex, links chromatin opening to ATM activation by facilitating ATM recruitment to the open chromatin regions of a panel of hepatic gene loci. These findings shed light on cellular responses to lineage conversion by revealing a function of the ATM-p53 pathway in sensing chromatin opening.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Shuyi
authors.initials: S
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Linying
authors.initials: L
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yimeng
authors.initials: Y
authors.lastname: Gao
authors.affiliation: CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiaoran
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Cen
authors.affiliation: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Rongxia
authors.initials: R
authors.lastname: Li
authors.affiliation: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zeng
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Lujian
authors.initials: L
authors.lastname: Liao
authors.affiliation: Department of Biology, South University of Science and Technology of China, Shenzhen, Guangdong 518055, China.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Hou
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Shaorong
authors.initials: S
authors.lastname: Gao
authors.affiliation: CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.|School of Life Science and Technology, Shanghai Tech University, 100 Haike Road, Shanghai 201210, China.
authors.forename: Lijian
authors.initials: L
authors.lastname: Hui
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D019070:Cell Lineage; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D008099:Liver / Q000166:cytology; D008297:Male; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000378:metabolism; D000072417:Protein Domains; D013623:Tail; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D009124:Muscle Proteins; D019913:Nuclear Localization Signals; C445179:SWI-SNF-B chromatin-remodeling complex; C494056:Smarcd2 protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D064007:Ataxia Telangiectasia Mutated Proteins