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

Gene. 2022 Sep 30:146928. doi: 10.1016/j.gene.2022.146928. Online ahead of print.ABSTRACTBone 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 did not affect alkaline phosphatase activity nor did it result in a unified expression response for standard osteoblast-related mRNA markers (e.g., Bglap, Ibsp, Omd, 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 ...

Source: Gene - October 3, 2022 Category: Genetics & Stem Cells Authors: Parisa Dashti Jeroen van de Peppel Roman Thaler Christopher R Paradise Gary S Stein Martin A Montecino Johannes P T M van Leeuwen Bram J van der Eerden Amel Dudakovic Andre J van Wijnen Source Type: research