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

Hiroki Takahashi, Ge Yang, Takeshi Yoneshiro, Yohei Abe, Ryo Ito, Chaoran Yang, Junna Nakazono, Mayumi Okamoto-Katsuyama, Aoi Uchida, Makoto Arai, Hitomi Jin, Hyunmi Choi, Myagmar Tumenjargal, Shiyu Xie, Ji Zhang, Hina Sagae, Yanan Zhao, Rei Yamaguchi, Yu Nomura, Yuichi Shimizu, Kaito Yamada, Satoshi Yasuda, Hiroshi Kimura, Toshiya Tanaka, Youichiro Wada, Tatsuhiko Kodama, Hiroyuki Aburatani, Min-Sheng Zhu, Takeshi Inagaki, Timothy F. Osborne, Takeshi Kawamura, Yasushi Ishihama, Yoshihiro Matsumura () and Juro Sakai ()
Additional contact information
Hiroki Takahashi: Tohoku University Graduate School of Medicine
Ge Yang: Tohoku University Graduate School of Medicine
Takeshi Yoneshiro: The University of Tokyo
Yohei Abe: The University of Tokyo
Ryo Ito: Tohoku University Graduate School of Medicine
Chaoran Yang: Tohoku University Graduate School of Medicine
Junna Nakazono: Kyoto University
Mayumi Okamoto-Katsuyama: The University of Tokyo
Aoi Uchida: The University of Tokyo
Makoto Arai: Tohoku University Graduate School of Medicine
Hitomi Jin: Tohoku University Graduate School of Medicine
Hyunmi Choi: Tohoku University Graduate School of Medicine
Myagmar Tumenjargal: Tohoku University Graduate School of Medicine
Shiyu Xie: Tohoku University Graduate School of Medicine
Ji Zhang: Tohoku University Graduate School of Medicine
Hina Sagae: Tohoku University Graduate School of Medicine
Yanan Zhao: Tohoku University Graduate School of Medicine
Rei Yamaguchi: Tohoku University Graduate School of Medicine
Yu Nomura: Tohoku University Graduate School of Medicine
Yuichi Shimizu: Tohoku University Graduate School of Medicine
Kaito Yamada: Tohoku University Graduate School of Medicine
Satoshi Yasuda: Tohoku University Graduate School of Medicine
Hiroshi Kimura: Tokyo Institute of Technology
Toshiya Tanaka: The University of Tokyo
Youichiro Wada: The University of Tokyo
Tatsuhiko Kodama: The University of Tokyo
Hiroyuki Aburatani: The University of Tokyo
Min-Sheng Zhu: Nanjing University
Takeshi Inagaki: The University of Tokyo
Timothy F. Osborne: Diabetes and Metabolism of the Johns Hopkins University School of Medicine
Takeshi Kawamura: The University of Tokyo
Yasushi Ishihama: Kyoto University
Yoshihiro Matsumura: Tohoku University Graduate School of Medicine
Juro Sakai: Tohoku University Graduate School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33363-0

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