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

Nat Commun. 2018 Apr 19;9(1):1566. doi: 10.1038/s41467-018-03868-8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acclimatization
  • Adipogenesis
  • Adipose Tissue, Brown / enzymology
  • Adipose Tissue, Brown / metabolism
  • Adipose Tissue, White / enzymology
  • Adipose Tissue, White / metabolism
  • Animals
  • Cold Temperature
  • Cold-Shock Response*
  • Female
  • Jumonji Domain-Containing Histone Demethylases / chemistry
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Phosphorylation
  • Signal Transduction
  • Thermogenesis*
  • Uncoupling Protein 1 / genetics
  • Uncoupling Protein 1 / metabolism

Substances

  • PPAR gamma
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • Jumonji Domain-Containing Histone Demethylases
  • Kdm3a protein, mouse