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.
Highlights
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)
We previously showed that JMJD1A integrates β-adrenergic-cAMP signaling with the peroxisome proliferator-activated receptor-γ (PPARγ) gene activation program through a mechanism where pS265-JMJD1A performs a scaffolding role to activate key PPARγ target genes required for thermogenesis in BAT13
BAT mediates acute and robust thermogenic activity, while subcutaneous white adipose tissue (scWAT)-derived beige adipocytes contribute to an adaptive response against chronic cold exposure
Summary
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). They proposed that the activation of Ucp[1] required JMJD1A demethylase activity, because BAR stimulation in a cultured line of brown adipocytes resulted in a decrease of H3K9me[2] on the Ucp[1] gene enhancer, and this effect was lost when JMJD1A levels were reduced by a knockdown approach This result was unexpected because Ucp[1] is constitutively expressed at a high basal level in BAT before cold stress, indicating that the Ucp[1] locus already has features of euchromatin. We showed that after phosphorylation, JMJD1A facilitated long-range chromatin interactions to facilitate BAR signal-dependent gene expression (i.e., through dynamic higher ordered chromatin structure)[13] This phosphorylation-dependent, but H3K9me[2] demethylation-independent BAR induction mechanism functions on top of the other chromatin regulatory events (e.g., histone acetylation13) that allow constitutive high expression of Ucp[1] in BAT
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