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The histone acetyltransferase Mof regulates Runx2 and Osterix for osteoblast differentiation

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Abstract

Osteoblast differentiation is regulated by various transcription factors, signaling molecules, and posttranslational modifiers. The histone acetyltransferase Mof (Kat8) is involved in distinct physiological processes. However, the exact role of Mof in osteoblast differentiation and growth remains unknown. Herein, we demonstrated that Mof expression with histone H4K16 acetylation increased during osteoblast differentiation. Inhibition of Mof by siRNA knockdown or small molecule inhibitor, MG149 which is a potent histone acetyltransferase inhibitor, reduced the expression level and transactivation potential of osteogenic key markers, Runx2 and Osterix, thus inhibiting osteoblast differentiation. Besides, Mof overexpression also enhanced the protein levels of Runx2 and Osterix. Mof could directly bind the promoter region of Runx2/Osterix to potentiate their mRNA levels, possibly through Mof-mediated H4K16ac to facilitate the activation of transcriptional programs. Importantly, Mof physically interacts with Runx2/Osterix for the stimulation of osteoblast differentiation. Yet, Mof knockdown showed indistinguishable effect on cell proliferation or apoptosis in MSCs and preosteoblast cells. Taken together, our results uncover Mof functioning as a novel regulator of osteoblast differentiation via the promotional effects on Runx2/Osterix and rationalize Mof as a potential therapeutic target, like possible application of inhibitor MG149 for the treatment of osteosarcoma or developing specific Mof activator to ameliorate osteoporosis.

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Funding

This work was supported by National Key R&D Program of China 2016YFE0129200, National Natural Science Foundation of China (Nos. 31571321, 81601337) and the Natural Science Foundation of Shandong Province, China (No. ZR2022MH003).

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  1. Jianmei Chen, Di Liu, and Bo Chen contributed equally to this work.

Authors and Affiliations

  1. Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, 266237, China

    Jianmei Chen, Hongying Zhu, Kun Liu, Lina Zhu, Xu Zhang & Xiangzhi Li

  2. School of Stomatology, Shandong University, Jinan, 250012, China

    Di Liu, Hongrui Liu & Minqi Li

  3. Qilu Hospital of Shandong University, Jinan, 250012, China

    Bo Chen & Danyang Li

  4. School of Pharmacy, Binzhou Medical University, Yantai, 264003, China

    Yang Yang

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  1. Jianmei Chen
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Contributions

Conceptualization, X.Z.L. and X.Z.; investigation, J.M.C., D.L., B.C., X.Z., H.Y.Z., and K.L.; methodology, J.M.C., D.L., B.C., Y.Y., D.Y.L., L.N.Z., H.R.L., and M.Q.L.; writing, J.M.C., X.Z., and X.Z.L. All authors have reviewed and approved the manuscript.

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Correspondence to Xu Zhang or Xiangzhi Li.

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Chen, J., Liu, D., Chen, B. et al. The histone acetyltransferase Mof regulates Runx2 and Osterix for osteoblast differentiation. Cell Tissue Res 393, 265–279 (2023). https://doi.org/10.1007/s00441-023-03791-5

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