Volume 27, No 5, May 2017

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 27 Issue 5, May 2017: 642-656   |  Open Access

ORIGINAL ARTICLES

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

Shuyi Ji^1,*, Linying Zhu^1,*, Yimeng Gao¹, Xiaoran Zhang², Yupeng Yan1, Jin Cen¹, Rongxia Li³, Rong Zeng³, Lujian Liao⁴, Chunhui Hou⁵, Yawei Gao⁶, Shaorong Gao⁶, Gang Wei² and Lijian Hui^1,7

¹State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
²CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
³Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
⁴Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China
⁵Department of Biology, South University of Science and Technology of China, Shenzhen, Guangdong 518055, China
⁶Clinical 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
⁷School of Life Science and Technology, Shanghai Tech University, 100 Haike Road, Shanghai 201210, China Correspondence: Lijian Hui, E-mail: ljhui@sibcb.ac.cn; Gang Wei,(weigang@picb.ac.cn)

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.

10.1038/cr.2017.36

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