Spatiotemporal dynamics of SETD5-containing NCoR–HDAC3 complex determines enhancer activation for adipogenesis

Matsumura, Yoshihiro; Itô, Ryo; Yajima, Ayumu; Yamaguchi, Rei; Tanaka, Toshiya; Kawamura, Takeshi; Magoori, Kenta; Abe, Yohei; Uchida, Aoi; Yoneshiro, Takeshi; Hirakawa, Hiromasa; Zhang, Ji; Arai, Makoto; Yang, Chaoran; Yang, Ge; Takahashi, Hiroki; Fujihashi, Hitomi; Nakaki, Ryo; Yamamoto, Shozo; Ota, Satoshi; Tsutsumi, Sadami; Inoue, Shinichi; Kimurâ, Hiroshi; Wada, Youichiro; Kodama, Tatsuhiko; Inagaki, Takeshi; Osborne, Timothy F.; Aburatani, Hiroyuki; Node, Koichi; Sakai, Juro

doi:10.1038/s41467-021-27321-5

Cited by 16 publications

(13 citation statements)

References 73 publications

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“…One of the main biological functions of HDAC3 is repression of transcription via histone deacetylation (Hogg et al 2021). Researchers have proven that the SETD5-containing NCOR-HDAC3 complex inhibits H3K27 acetylation and enhancer activation of 2 adipogenic genes, Cebpα and Pparγ , early during adipogenesis, which is similar to our findings (Matsumura et al 2021). Furthermore, a previous study showed an increase in inflammatory cytokines in Ncor1 -deficient macrophages when stimulated by PPARγ agonists, thereby exacerbating atherosclerosis (Oppi et al 2020).…”

Section: Discussionsupporting

confidence: 92%

Ncor1 Deficiency Promotes Osteoclastogenesis and Exacerbates Periodontitis

Meng

Wang

et al. 2022

J Dent Res

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Nuclear receptor corepressor 1 ( Ncor1) has been reported to regulate different transcription factors in different biological processes, including metabolism, inflammation, and circadian rhythms. However, the role of Ncor1 in periodontitis has not been elucidated. The aims of the present study were to investigate the role of Ncor1 in experimental periodontitis and to explore the underlying mechanisms through an experimental periodontitis model in myeloid cell–specific Ncor1-deficient mice. Myeloid cell–specific Ncor1 knockout (MNKO) mice were generated, and experimental periodontitis induced by ligation using 5-0 silk sutures was established. Ncor1 flox/flox mice were used as littermate controls (LC). Histological staining and micro–computed tomography scanning were used to evaluate osteoclastogenesis and alveolar bone resorption. Flow cytometry was conducted to observe the effect of Ncor1 on myeloid cells. RNA sequencing was used to explore the differentially targeted genes in osteoclastogenesis in the absence of Ncor1. Coimmunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP) experiments, and dual luciferase assays were performed to explore the relationship between NCoR1 and the targeted gene. Alveolar bone resorption in the MNKO mice was significantly greater than that in the LC mice after periodontitis induction and osteoclastogenesis in vitro. The percentage of CD11b+ cells, particularly CD11b+ Ly6G+ neutrophils, was substantially higher in gingival tissues in the MNKO mice than in the LC mice. Results of RNA sequencing demonstrated that CCAAT enhancer binding protein α ( Cebpα) was one of the most differentially expressed genes between the MNKO and LC groups. Mechanistically, Co-IP assays, ChIP experiments, and dual luciferase assays revealed that NCOR1 interacted with peroxisome proliferator-activated receptor gamma (PPARγ) and cooperated with HDAC3 to control the transcription of Cebpα. In conclusion, Ncor1 deficiency promoted osteoclast and neutrophil formation in mice with experimental periodontitis. It regulated the transcription of Cebpα via PPARγ to promote osteoclast differentiation.

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Section: Discussionsupporting

confidence: 92%

Ncor1 Deficiency Promotes Osteoclastogenesis and Exacerbates Periodontitis

Meng

Wang

et al. 2022

J Dent Res

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“…Mice were maintained in a temperature-and humidity-controlled environment under a 12 h light/12 h dark cycle (08:00-20:00) at constant temperature (23 °C) with free access to food and water. Animals were fed a normal chow diet (CE-2, CLEA Japan Inc.) from the age of 4 weeks or HFD, consisting of 58.0% fat, 15.0% protein, and 27.0% carbohydrate, from the age of 5 to 7 weeks as described previously [61][62][63] . For chronic cold exposure experiments, animals were single-caged and exposed to 12 °C for one week.…”

Section: Animal Experimentsmentioning

confidence: 99%

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

et al. 2022

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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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“…It belongs to SET-domain lysine methyltransferase superfamily which functions to methylate certain histone lysine residues, resulting in regulating the expression of genes. However, there is evidence that SETD5 lacks the methyltransferase activity but scaffolds a corepressor complex, including HDAC3, NCoR, G9a, and PAF1, which couples selective deacetylation of H3K9ac with methylation of this residue (13)(14)(15). The yeast SET3 and SET4, Drosophila UpSET, and human MLL5 are homologous to SETD5 over their SET domains and, except for SETD5, contain a PHD finger (Figure 1).…”

Section: Structural Features Of Setd5mentioning

confidence: 99%

Structure, activity and function of the lysine methyltransferase SETD5

Hou

Zhang

et al. 2023

Front. Endocrinol.

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SET domain-containing 5 (SETD5) is an uncharacterized member of the protein lysine methyltransferase family and is best known for its transcription machinery by methylating histone H3 on lysine 36 (H3K36). These well-characterized functions of SETD5 are transcription regulation, euchromatin formation, and RNA elongation and splicing. SETD5 is frequently mutated and hyperactive in both human neurodevelopmental disorders and cancer, and could be down-regulated by degradation through the ubiquitin-proteasome pathway, but the biochemical mechanisms underlying such dysregulation are rarely understood. Herein, we provide an update on the particularities of SETD5 enzymatic activity and substrate specificity concerning its biological importance, as well as its molecular and cellular impact on normal physiology and disease, with potential therapeutic options.

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Spatiotemporal dynamics of SETD5-containing NCoR–HDAC3 complex determines enhancer activation for adipogenesis

Cited by 16 publications

References 73 publications

Ncor1 Deficiency Promotes Osteoclastogenesis and Exacerbates Periodontitis

Ncor1 Deficiency Promotes Osteoclastogenesis and Exacerbates Periodontitis

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

Structure, activity and function of the lysine methyltransferase SETD5

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