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The histone methyltransferase ASH1L protects against bone loss by inhibiting osteoclastogenesis

Cell Death & Differentiation (2024)Cite this article

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Abstract

Absent, small, or homeotic1-like (ASH1L) is a histone lysine methyltransferase that generally functions as a transcriptional activator in controlling cell fate. So far, its physiological relevance in bone homeostasis and osteoclast differentiation remains elusive. Here, by conditional deleting Ash1l in osteoclast progenitors of mice, we found ASH1L deficiency resulted in osteoporosis and potentiation of osteoclastogenesis in vivo and in vitro. Mechanistically, ASH1L binds the promoter of the Src homology 3 and cysteine-rich domain 2 (Stac2) and increases the gene’s transcription via histone 3 lysine 4 (H3K4) trimethylation modification, thus augmenting the STAC2’s protection against receptor activator of nuclear factor kB ligand (RANKL)-initiated inflammation during osteoclast formation. Collectively, we demonstrate the first piece of evidence to prove ASH1L as a critical checkpoint during osteoclastogenesis. The work sheds new light on our understanding about the biological function of ASH1L in bone homeostasis, therefore providing a valuable therapeutic target for the treatment of osteoporosis or inflammatory bone diseases.

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Fig. 1: Myeloid-specific Ash1l knockout mice exhibit osteoporotic phenotypes.
Fig. 2: ASH1L deficiency promotes osteoclast differentiation ex vivo.
Fig. 3: ASH1L negatively regulates osteoclast formation in vitro and inhibits RANKL-induced inflammatory signaling activation.
Fig. 4: Stac2 gene expression coincides with that of Ash1l during osteoclast differentiation.
Fig. 5: ASH1L upregulates Stac2 expression via its H3K4 methyltransferase activity and potentiates STAC2’s inhibition against osteoclast formation.
Fig. 6: Ash1l expression declines in bone tissue and BMMs during aging process and is downregulated by miR-142-3p.
Fig. 7: Correlation analysis for Ash1l gene expression in inflammatory bone diseases.

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Data availability

RNA-seq data and CUT&Tag-seq data have been deposited at the NCBI Sequence Read Archive at https://www.ncbi.nlm.nih.gov/sra with accession number PRJNA947264 and PRJNA1065086. Other data in this study are available upon request from the corresponding author.

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Funding

This work is supported by grants from the National Natural Science Foundation of China (No. 82100945) and the CAMS Innovation Fund for Medical Sciences (CIFMS) (Nos. 2021-I2M-1-055, 2021-I2M-1-030).

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Author notes

  1. These authors contributed equally: Xiaoli Zhao, Shuai Lin, Hangjiang Ren.

Authors and Affiliations

  1. Department of Biochemistry, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Xiaoli Zhao, Shuai Lin, Hangjiang Ren, Shenghui Sun, Liyun Zheng & Zhen Wang

  2. Department of Orthodontics, School and Hospital of Stomatology, Peking University, Beijing, China

    Shuai Lin

  3. Department of Biochemistry, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, USA

    Lin-Feng Chen

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Contributions

Conception and design: ZW, XZ, SL; Development of methodology: XZ, SL, HR, SS, ZW; Acquisition of data: XZ, SL, HR, SS, LZ; Analysis and interpretation of data: XZ, SL, HR, ZW; Administrative, technical, or material support: ZW, LC. Writing of the manuscript: ZW, XZ, HR, LC. All the authors have authorized the submission.

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Correspondence to Zhen Wang.

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Zhao, X., Lin, S., Ren, H. et al. The histone methyltransferase ASH1L protects against bone loss by inhibiting osteoclastogenesis. Cell Death Differ (2024). https://doi.org/10.1038/s41418-024-01274-w

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