The lysine methyltransferases SET and MYND domain containing 2 (Smyd2) and Enhancer of Zeste 2 (Ezh2) co-regulate osteoblast proliferation and mineralization.

Autor: Dashti P; Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA., van de Peppel J; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands., Thaler R; Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA., Paradise CR; Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA., Stein GS; Department of Biochemistry, University of Vermont, Burlington, VT, USA., Montecino MA; Institute of Biomedical Sciences, Universidad Andres Bello, Santiago, Chile., van Leeuwen JPTM; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands., van der Eerden BJ; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands., Dudakovic A; Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA. Electronic address: Dudakovic.Amel@mayo.edu., van Wijnen AJ; Department of Biochemistry, University of Vermont, Burlington, VT, USA. Electronic address: andre.vanwijnen@uvm.edu.
Jazyk: angličtina
Zdroj: Gene [Gene] 2023 Jan 30; Vol. 851, pp. 146928. Date of Electronic Publication: 2022 Sep 30.
DOI: 10.1016/j.gene.2022.146928
Abstrakt: Bone formation is controlled by histone modifying enzymes that regulate post-translational modifications on nucleosomal histone proteins and control accessibility of transcription factors to gene promoters required for osteogenesis. Enhancer of Zeste homolog 2 (EZH2/Ezh2), a histone H3 lysine 27 (H3K27) methyl transferase, is a suppressor of osteoblast differentiation. Ezh2 is regulated by SET and MYND domain-containing protein 2 (SMYD2/Smyd2), a lysine methyltransferase that modifies both histone and non-histone proteins. Here, we examined whether Smyd2 modulates Ezh2 suppression of osteoblast differentiation. Musculoskeletal RNA-seq data show that SMYD2/Smyd2 is the most highly expressed SMYD/Smyd member in human bone tissues and mouse osteoblasts. Smyd2 loss of function analysis in mouse MC3T3 osteoblasts using siRNA depletion enhances proliferation and calcium deposition. Loss of Smyd2 protein does not affect alkaline phosphatase activity nor does it result in a unified expression response for standard osteoblast-related mRNA markers (e.g., Bglap, Ibsp, Spp1, Sp7), indicating that Smyd2 does not directly control osteoblast differentiation. Smyd2 protein depletion enhances levels of the osteo-suppressive Ezh2 protein and H3K27 trimethylation (H3K27me3), as expected from increased cell proliferation, while elevating the osteo-inductive Runx2 protein. Combined siRNA depletion of both Smyd2 and Ezh2 protein is more effective in promoting calcium deposition when compared to loss of either protein. Collectively, our results indicate that Smyd2 inhibits proliferation and indirectly the subsequent mineral deposition by osteoblasts. Mechanistically, Smyd2 represents a functional epigenetic regulator that operates in parallel to the suppressive effects of Ezh2 and H3K27 trimethylation on osteoblast differentiation.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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