Fasting-induced JMJD3 histone demethylase epigenetically activates mitochondrial fatty acid β-oxidation
Sunmi Seok, Young-Chae Kim, Sangwon Byun, Sunge Choi, Zhen Xiao, Naoki Iwamori, Yang Zhang, Chaochen Wang, Jian Ma, Kai Ge, Byron Kemper, Jongsook Kim Kemper
Sunmi Seok, Young-Chae Kim, Sangwon Byun, Sunge Choi, Zhen Xiao, Naoki Iwamori, Yang Zhang, Chaochen Wang, Jian Ma, Kai Ge, Byron Kemper, Jongsook Kim Kemper
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Research Article Cell biology Metabolism

Fasting-induced JMJD3 histone demethylase epigenetically activates mitochondrial fatty acid β-oxidation

Abstract

Jumonji D3 (JMJD3) histone demethylase epigenetically regulates development and differentiation, immunity, and tumorigenesis by demethylating a gene repression histone mark, H3K27-me3, but a role for JMJD3 in metabolic regulation has not been described. SIRT1 deacetylase maintains energy balance during fasting by directly activating both hepatic gluconeogenic and mitochondrial fatty acid β-oxidation genes, but the underlying epigenetic and gene-specific mechanisms remain unclear. In this study, JMJD3 was identified unexpectedly as a gene-specific transcriptional partner of SIRT1 and epigenetically activated mitochondrial β-oxidation, but not gluconeogenic, genes during fasting. Mechanistically, JMJD3, together with SIRT1 and the nuclear receptor PPARα, formed a positive autoregulatory loop upon fasting-activated PKA signaling and epigenetically activated β-oxidation–promoting genes, including Fgf21, Cpt1a, and Mcad. Liver-specific downregulation of JMJD3 resulted in intrinsic defects in β-oxidation, which contributed to hepatosteatosis as well as glucose and insulin intolerance. Remarkably, the lipid-lowering effects by JMJD3 or SIRT1 in diet-induced obese mice were mutually interdependent. JMJD3 histone demethylase may serve as an epigenetic drug target for obesity, hepatosteatosis, and type 2 diabetes that allows selective lowering of lipid levels without increasing glucose levels.

Authors

Sunmi Seok, Young-Chae Kim, Sangwon Byun, Sunge Choi, Zhen Xiao, Naoki Iwamori, Yang Zhang, Chaochen Wang, Jian Ma, Kai Ge, Byron Kemper, Jongsook Kim Kemper

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Figure 2

JMJD3 is a gene-specific transcriptional partner of SIRT1 and epigenetically activates mitochondrial β-oxidation–promoting genes.

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JMJD3 is a gene-specific transcriptional partner of SIRT1 and epigenetic...
(A and B) Primary mouse hepatocytes were infected with lentivirus expressing JMJD3 shRNA or control shRNA, and the cells were treated with Fsk for 6 hours. (A) JMJD3 and actin detected by IB in cells infected with lenti-Ctl or lenti-shJMJD3 (left). Volcano plot indicates down- or upregulated genes as determined by RNA-seq. (B) mRNA levels of selected genes were determined by qRT-PCR. (C–E) Mice were fasted for 16 hours or re-fed for 6 hours after fasting. (C) Occupancy of JMJD3 and SIRT1 at the indicated genes was determined by ChIP. (D) Re-ChIP: Liver chromatin was immunoprecipitated with SIRT1 antibody, eluted, and reprecipitated with SIRT1 or JMJD3 antibody. (E) Ratios of methylated H3K27-me3 and H3K4-me3 to total histone H3 at the indicated genes were determined by ChIP. (F) Ratios of methylated H3K27-me3 to total H3 at the indicated genes were determined by ChIP in hepatocytes that were infected with lenti-shRNA for JMJD3 or control shRNA and treated with Fsk for 3 hours. n = 6 (B), n = 3 mice/group (C–E), and n = 3 (F). Data represent the mean ± SEM. *P < 0.05 and **P < 0.01, by Student’s t test (B), Mann-Whitney U test (C–E), and 2-way ANOVA with the FDR text (F). Gluconeo, gluconeogenesis.