Histone demethylase JMJD1A coordinates acute and chronic adaptation to cold stress via thermogenic phospho-switch

Yohei Abe, Yosuke Fujiwara, Hiroki Takahashi, Yoshihiro Matsumura, Tomonobu Sawada, Shuying Jiang, Ryo Nakaki, Aoi Uchida, Noriko Nagao, Makoto Naito, Shingo Kajimura, Hiroshi Kimura, Timothy F. Osborne, Hiroyuki Aburatani, Tatsuhiko Kodama, Takeshi Inagaki () and Juro Sakai ()
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Yohei Abe: The University of Tokyo
Yosuke Fujiwara: The University of Tokyo
Hiroki Takahashi: The University of Tokyo
Yoshihiro Matsumura: The University of Tokyo
Tomonobu Sawada: The University of Tokyo
Shuying Jiang: Niigata College of Medical Technology
Ryo Nakaki: Rhelixa Inc.
Aoi Uchida: The University of Tokyo
Noriko Nagao: The University of Tokyo
Makoto Naito: Niigata Medical Center
Shingo Kajimura: University of California, San Francisco
Hiroshi Kimura: Tokyo Institute of Technology
Timothy F. Osborne: Sanford-Burnham Medical Research Institute
Hiroyuki Aburatani: The University of Tokyo
Tatsuhiko Kodama: The University of Tokyo
Takeshi Inagaki: The University of Tokyo
Juro Sakai: The University of Tokyo

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract In acute cold stress in mammals, JMJD1A, a histone H3 lysine 9 (H3K9) demethylase, upregulates thermogenic gene expressions through β-adrenergic signaling in brown adipose tissue (BAT). Aside BAT-driven thermogenesis, mammals have another mechanism to cope with long-term cold stress by inducing the browning of the subcutaneous white adipose tissue (scWAT). Here, we show that this occurs through a two-step process that requires both β-adrenergic-dependent phosphorylation of S265 and demethylation of H3K9me2 by JMJD1A. The histone demethylation-independent acute Ucp1 induction in BAT and demethylation-dependent chronic Ucp1 expression in beige scWAT provides complementary molecular mechanisms to ensure an ordered transition between acute and chronic adaptation to cold stress. JMJD1A mediates two major signaling pathways, namely, β-adrenergic receptor and peroxisome proliferator-activated receptor-γ (PPARγ) activation, via PRDM16-PPARγ-P-JMJD1A complex for beige adipogenesis. S265 phosphorylation of JMJD1A, and the following demethylation of H3K9me2 might prove to be a novel molecular target for the treatment of metabolic disorders, via promoting beige adipogenesis.

Date: 2018
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DOI: 10.1038/s41467-018-03868-8

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