Abstract
BackgroundMMP-9 plays a direct role in the activation of pro-osteoclastogenic genes by cleaving histone H3N-terminal tail (H3NT) and altering chromatin architecture. Although H3 acetylation at K18 has been shown to stimulate MMP-9 enzymatic activity toward H3NT, nothing is known about the influence of other H3NT modifications on this epigenetic reaction.ResultsWe show that H3 monomethylation at lysine 27 (H3K27me1) is essential for MMP-9-dependent H3NT proteolysis during RANKL-induced osteoclast differentiation. Through the recognition of H3K27me1 mark, MMP-9 localizes and generates H3NT proteolysis at the genes encoding osteoclast differentiation factors. By using RNAi and small molecule inhibitor approaches, we also confirmed that G9a is the major methyltransferase to catalyze H3K27me1 for MMP-9-dependent H3NT proteolysis and trigger the expression of osteoclast-specific genes.ConclusionsOur data establish new functions for G9a-mediated H3K27me1 in MMP-9-dependent H3NT proteolysis and demonstrate how histone modification can be exploited to regulate osteoclastogenic gene expression at the molecular level. Further studies are warranted to investigate the detailed mechanism by which G9a overexpression with concomitant dysregulation of osteoclastogenesis contributes to the pathogenesis of bone disorders.
Highlights
Matrix metalloproteinases (MMPs)-9 plays a direct role in the activation of pro-osteoclastogenic genes by cleaving histone H3Nterminal tail (H3NT) and altering chromatin architecture
H3K27me1 is necessary for MMP‐9‐dependent H3NT proteolysis of nucleosome substrates We have recently demonstrated that p300/CBP-mediated H3K18 acetylation (H3K18ac) neutralizes the charged lysine residue at the primary cleavage site (P1) of MMP-9 and amplifies MMP-9 enzymatic activity toward both free and nucleosomal H3 substrates [20]
Since H3NTs are subject to other types of modifications such as methylation and phosphorylation, investigating their possible effects on MMP-9-dependent H3NT proteolysis should be a logical extension of our study (Fig. 1a)
Summary
MMP-9 plays a direct role in the activation of pro-osteoclastogenic genes by cleaving histone H3Nterminal tail (H3NT) and altering chromatin architecture. Osteoblasts are mononucleated mesenchymal stem cells that form bone matrix, whereas osteoclasts are bone-resorbing multinucleated cells that differentiate from hematopoietic progenitors of the myeloid lineage [3,4,5]. Osteoclast differentiation is induced by receptor activator of NF-κB ligand (RANKL), which is expressed as a membrane-bound protein in osteoblasts and provides osteoclast-specific differentiation signals [6, 7]. As for other eukaryotic genes, osteoclastogenic gene expression occurs in the context of chromatin, where DNA is wound around histone proteins to form chromatin structure [11, 12].
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