Histone demethylase JMJD1C is phosphorylated by mTOR to activate de novo lipogenesis

• Published in: Nature communications Vol. 11; no. 1; pp. 796 - 16
• Main Authors: Viscarra, Jose A., Wang, Yuhui, Nguyen, Hai P., Choi, Yoon Gi, Sul, Hei Sook
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-02-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 38/39; 38/77; 631/443/319; 64/60; 692/699/2743/393; 82/1; 82/29; 82/58; 82/83; 96/106; 96/109; 96/95; Acyltransferase; Animals; Chromatin; Diet, High-Fat - adverse effects; Eating - genetics; Eating - physiology; Fatty acids; Fatty-acid synthase; Female; Gene Expression Regulation; Genome-Wide Association Study; Glycerol; Glycerol-3-phosphate; Hep G2 Cells; Hepatocytes; Histone H3; Histones; Histones - metabolism; Humanities and Social Sciences; Humans; Insulin; Insulin - metabolism; Insulin - pharmacology; Insulin Resistance; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - metabolism; Lipogenesis; Lipogenesis - drug effects; Lipogenesis - genetics; Lipogenesis - physiology; Liver; Lysine - metabolism; Male; Metabolic rate; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Oxidoreductases, N-Demethylating - genetics; Oxidoreductases, N-Demethylating - metabolism; Phosphorylation; Promoter Regions, Genetic; Science; Science (multidisciplinary); Sterol regulatory element-binding protein; TOR protein; TOR Serine-Threonine Kinases - metabolism; Transcription activation; Transcription factors; Triglycerides; Triglycerides - blood; Triglycerides - metabolism; Upstream Stimulatory Factors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-14617-1

Fatty acid and triglyceride synthesis increases greatly in response to feeding and insulin. This lipogenic induction involves coordinate transcriptional activation of various enzymes in lipogenic pathway, including fatty acid synthase and glycerol-3-phosphate acyltransferase. Here, we show that JMJD1C is a specific histone demethylase for lipogenic gene transcription in liver. In response to feeding/insulin, JMJD1C is phosphorylated at T505 by mTOR complex to allow direct interaction with USF-1 for recruitment to lipogenic promoter regions. Thus, by demethylating H3K9me2, JMJD1C alters chromatin accessibility to allow transcription. Consequently, JMJD1C promotes lipogenesis in vivo to increase hepatic and plasma triglyceride levels, showing its role in metabolic adaption for activation of the lipogenic program in response to feeding/insulin, and its contribution to development of hepatosteatosis resulting in insulin resistance.
In response to insulin, liver cells increase de novo lipogenesis via the transcription factors USF-1 and SREBP. Here the authors show that USF-1 recruits JMJD1C, after its phosphorylation by mTOR, to lipogenic promoters where JMJD1C demethylates histone H3, contributing to lipogenesis by an epigenetic mechanism.