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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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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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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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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DOI: https://doi.org/10.1038/s41418-024-01274-w