MLL3/MLL4-Associated PAGR1 Regulates Adipogenesis by Controlling Induction of C/EBPI3 and C/EBPS

Transcription factors C/EBP beta and C/EBP beta are induced within hours after ini-tiation of adipogenesis in culture. They directly promote the expression of master adipo-genic transcription factors peroxisome proliferator-activated receptor gamma (PPAR gamma) and C/EBP alpha and are required for adipogenesis in vivo. However, the mechanism that controls the induction of C/EBP beta and C/EBP delta remains elusive. We previously showed that histone methyltransferases MLL3/MLL4 and associated PTIP are required for the induction of PPAR gamma and C/EBP alpha during adipogenesis. Here, we show MLL3/MLL4/PTIP-associated pro-tein PAGR1 (also known as PA1) cooperates with phosphorylated CREB and ligand-activated glucocorticoid receptor to directly control the induction of C/EBP beta and C/EBP delta in the early phase of adipogenesis. Deletion of Pagr1 in white and brown preadipocytes prevents the induction of C/EBP beta and C/EBP delta and leads to severe defects in adipogene-sis. Adipogenesis defects in PAGR1-deficient cells can be rescued by the ectopic expression of C/EBP beta or PPAR gamma. Finally, the deletion of Pagr1 in Myf5(+) precursor cells impairs brown adipose tissue and muscle development. Thus, by controlling the induction of C/EBP beta and C/EBP delta, PAGR1 plays a critical role in adipogenesis.