Baf60b-mediated ATM-p53 activation blocks cell identity conversion by sensing chromatin opening

• Published in: Cell research Vol. 27; no. 5; pp. 642 - 656
• Main Authors: Ji, Shuyi, Zhu, Linying, Gao, Yimeng, Zhang, Xiaoran, Yan, Yupeng, Cen, Jin, Li, Rongxia, Zeng, Rong, Liao, Lujian, Hou, Chunhui, Gao, Yawei, Gao, Shaorong, Wei, Gang, Hui, Lijian
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.05.2017
• Subjects: Animals; Ataxia Telangiectasia Mutated Proteins - metabolism; Cell Lineage; Cell Nucleus - metabolism; Chromatin - metabolism; Chromatin Assembly and Disassembly; Chromosomal Proteins, Non-Histone - metabolism; Fibroblasts - metabolism; Liver - cytology; Male; Mice, Inbred C57BL; Muscle Proteins - metabolism; Nuclear Localization Signals - metabolism; Original; Protein Domains; Tail; Transcription Factors - metabolism; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2017.36

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-specif- ic transcription factors Foxa3, Hnfla 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 chro- matin 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 find- ings shed light on cellular responses to lineage conversion by revealing a function of the ATM-p53 pathway in sensing chromatin opening.