Journal
CELL RESEARCH
Volume 27, Issue 5, Pages 642-656Publisher
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/cr.2017.36
Keywords
Baf60b; ATM; p53; chromatin remodeling; lineage conversion; hepatic conversion
Categories
Funding
- National Natural Science Foundation of China [31225016, 91319307, 81471948]
- Ministry of Science and Technology of China [2013CB967103, 2012CB945001]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA01030601]
- Science and Technology Commission of Shanghai Municipality [14XD1404200, 15JC1400200]
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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, Hnf1 alpha 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.
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