MAT2 Orchestrates the Epigenetic Identity Program of Thermogenic Adipocytes and Creatine-Driven Thermogenesis through the PRDM16 Complex
Brown and beige adipocytes dissipate energy through thermogenesis, providing a defense against obesity and metabolic disorders. PR domain-containing 16 (PRDM16) is a transcriptional co-regulator that maintains thermogenic fat cell identity by forming a complex with transcriptional and epigenetic factors. While uncoupling protein 1 (UCP1) is a major mediator of adipocyte thermogenesis, UCP1-independent thermogenic cycles, including futile creatine cycle, have been identified. However, the mechanisms by which the PRDM16 complex controls both cell identity and creatine-driven thermogenesis remain unknown. Here we identify methionine adenosyltransferase 2 (MAT2) as an essential enzyme in the PRDM16 complex. In the nucleus of the adipocytes, MAT2 and PRDM16 associates with euchromatic histone-lysine N-methyltransferase 1 (EHMT1) to maintain the cell identity by repressing muscle- and white adipose-specific gene program via histone methylation. In the cytoplasm, MAT2 and PRDM16 interacts with guanidinoacetate N-methyltransferase (GAMT), a key enzyme in the creatine biosynthetic pathway. Importantly, chromatin immunoprecipitation followed by next generation sequencing analysis (ChIP-seq) reveals that Gamt is a direct transcriptional target of PRDM16. This complex contributes to UCP1-independent thermogenesis via creatine synthesis. Ablation of MAT2A, a catalytic subunit of MAT2, leads to a loss of brown and beige fat formation and disrupts adaptive thermogenesis in mice. Moreover, reanalysis of publicly available RNA-seq data reveals MAT2 expression is negatively correlated with obesity in human white adipose tissues, implying a role of MAT2 in adipose tissue metabolism.