Adipogenic differentiation and inflammatory response is orchestrated by regulating euchromatic histone methyltransferases.

Abstract

Euchromatic histone methyltransferases (EHMT1/2) play a key role in adipogenesis by regulating gene expression. While the downstream gene functions of EHMTs in adipogenic differentiation have been studied, their regulation and precise individual contributions remain elusive. We discovered the existence of a regulatory mechanism, wherein EHMT1 governs the interdependent expression of itself and the master regulator PPAR during the early phase of adipogenesis. In later stages, EHMT2 levels decline along with reduction in H3K9 dimethylation. Alteration of above sequence of events alone or in the presence of saturated-fatty acids lead to precocious induction of high levels of PPAR, accelerated adipogenesis and hypertrophic adipocytes with a pro-inflammatory phenotype. Countering the decrease in EHMTs effectively abrogated the inflammatory response of the adipocytes. Accordingly, induction of obesity by a high fat diet was sufficient to downregulate H3K9me2 levels and expression of EHMTs along with enhanced IL-6 generation. Taken together, our studies reveal a critical regulatory role played by EHMTs, which coordinates adipogenesis and obesity-induced inflammation.