RNA-sequence analysis of JMJD1A target genes in subcutanous white adipose tissue.
Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of ß-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to ß-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism. Overall design: Mice were individually caged in a thermostatic chamber and allowed to acclimate to thermal neutrality (30°C) for 1 week prior to the cold exposure experiments. Then, the mice were placed in a chamber maintained at either 30°C or 8°C with ad libitum access to food and water for 1 week. The mice were sacrificed and subcutanous adipose tissues were harvested and snap frozen in liquid nitrogen. The tissues were subjected to RNA extraction and RNA-sequence analysis using Illumina HiSeq 2500.