期刊
MOLECULAR CELL
卷 75, 期 2, 页码 357-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2019.05.019
关键词
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资金
- Canada Foundation for Innovation
- Dr. John R. and Clara M. Fraser Memorial Trust
- Terry Fox Foundation (TFF Oncometabolism Team Grant) [1048]
- Terry Fox Foundation (Foundation du Cancer du Sein du Quebec)
- McGill University
- NIH [HHSN276201200017C, R01GM094263, R01DK078081]
- NIH F31 Ruth-Kirschstein predoctoral fellowship
- Claudia Adams Barr Award in Innovative Basic Cancer Research
Carbohydrate response element binding protein (ChREBP) is a key transcriptional regulator of de novo lipogenesis (DNL) in response to carbohydrates and in hepatic steatosis. Mechanisms underlying nutrient modulation of ChREBP are under active investigation. Here we identify host cell factor 1 (HCF-1) as a previously unknown ChREBP-interacting protein that is enriched in liver biopsies of nonalcoholic steatohepatitis (NASH) patients. Biochemical and genetic studies show that HCF-1 is O-GlcNAcylated in response to glucose as a prerequisite for its binding to ChREBP and subsequent recruitment of OGT, ChREBP O-GlcNAcylation, and activation. The HCF-1: ChREBP complex resides at lipogenic gene promoters, where HCF-1 regulates H3K4 trimethylation to prime recruitment of the Jumonji C domain-containing histone demethylase PHF2 for epigenetic activation of these promoters. Overall, these findings define HCF-1's interaction with ChREBP as a previously unappreciated mechanism whereby glucose signals are both relayed to ChREBP and transmitted for epigenetic regulation of lipogenic genes.
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