MYPT1-PP1β phosphatase negatively regulates both chromatin landscape and co-activator recruitment for beige adipogenesis

Protein kinase A promotes beige adipogenesis downstream from beta-adrenergic receptor signaling by phosphorylating proteins, including histone H3 lysine 9 (H3K9) demethylase JMJD1A. To ensure homeostasis, this process needs to be reversible however, this step is not well understood. We show that myosin phosphatase target subunit 1- protein phosphatase 1 beta (MYPT1-PP1 beta) phosphatase activity is inhibited via PKA-dependent phosphorylation, which increases phosphorylated JMJD1A and beige adipogenesis. Mechanistically, MYPT1-PP1 beta depletion results in JMJD1A-mediated H3K9 demethylation and activation of the Ucp1 enhancer/promoter regions. Interestingly, MYPT1-PP1 beta also dephosphorylates myosin light chain which regulates actomyosin tension-mediated activation of YAP/TAZ which directly stimulates Ucp1 gene expression. Pre-adipocyte specific Mypt1 deficiency increases cold tolerance with higher Ucp1 levels in subcutaneous white adipose tissues compared to control mice, confirming this regulatory mechanism in vivo. Thus, we have uncovered regulatory cross-talk involved in beige adipogenesis that coordinates epigenetic regulation with direct activation of the mechano-sensitive YAP/TAZ transcriptional co-activators. How beta-AR signaling coordinates epigenetic and transcriptional pathways is unknown. Here the authors show that cold-induced beta-AR signaling negatively regulates MYPT1-PP1 beta phosphatase activity to orchestrate both pathways for beige adipogenesis.

Automated summary

Protein kinase A promotes beige adipogenesis by phosphorylating proteins, including histone H3 lysine 9 demethylase JMJD1A. This process needs to be reversible and is regulated by MYPT1-PP1β phosphatase activity. This study uncovers regulatory cross-talk involved in beige adipogenesis that coordinates epigenetic regulation with direct activation of YAP/TAZ transcriptional co-activators.