TY - JOUR
T1 - MYPT1-PP1β phosphatase negatively regulates both chromatin landscape and co-activator recruitment for beige adipogenesis
AU - Takahashi, Hiroki
AU - Yang, Ge
AU - Yoneshiro, Takeshi
AU - Abe, Yohei
AU - Ito, Ryo
AU - Yang, Chaoran
AU - Nakazono, Junna
AU - Okamoto-Katsuyama, Mayumi
AU - Uchida, Aoi
AU - Arai, Makoto
AU - Jin, Hitomi
AU - Choi, Hyunmi
AU - Tumenjargal, Myagmar
AU - Xie, Shiyu
AU - Zhang, Ji
AU - Sagae, Hina
AU - Zhao, Yanan
AU - Yamaguchi, Rei
AU - Nomura, Yu
AU - Shimizu, Yuichi
AU - Yamada, Kaito
AU - Yasuda, Satoshi
AU - Kimura, Hiroshi
AU - Tanaka, Toshiya
AU - Wada, Youichiro
AU - Kodama, Tatsuhiko
AU - Aburatani, Hiroyuki
AU - Zhu, Min Sheng
AU - Inagaki, Takeshi
AU - Osborne, Timothy F.
AU - Kawamura, Takeshi
AU - Ishihama, Yasushi
AU - Matsumura, Yoshihiro
AU - Sakai, Juro
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Protein kinase A promotes beige adipogenesis downstream from β-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 1β (MYPT1-PP1β) phosphatase activity is inhibited via PKA-dependent phosphorylation, which increases phosphorylated JMJD1A and beige adipogenesis. Mechanistically, MYPT1-PP1β depletion results in JMJD1A-mediated H3K9 demethylation and activation of the Ucp1 enhancer/promoter regions. Interestingly, MYPT1-PP1β 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.
AB - Protein kinase A promotes beige adipogenesis downstream from β-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 1β (MYPT1-PP1β) phosphatase activity is inhibited via PKA-dependent phosphorylation, which increases phosphorylated JMJD1A and beige adipogenesis. Mechanistically, MYPT1-PP1β depletion results in JMJD1A-mediated H3K9 demethylation and activation of the Ucp1 enhancer/promoter regions. Interestingly, MYPT1-PP1β 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.
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U2 - 10.1038/s41467-022-33363-0
DO - 10.1038/s41467-022-33363-0
M3 - Article
C2 - 36175407
AN - SCOPUS:85138869326
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5715
ER -