Epigenetic Control of Mesenchymal Stem Cell Fate Decision via Histone Methyltransferase Ash1l

Abstract

Previous research indicates that knocking out absent, small, or homeotic-like (Ash1l) in mice, a histone 3 lysine 4 (H3K4) trimethyltransferase, can result in arthritis with more severe cartilage and bone destruction. Research has documented the essential role of Ash1l in stem cell fate decision such as hematopoietic stem cells and the progenitors of keratinocytes. Following up on those insights, our research seeks to document the function of Ash1l in skeletal formation, specifically whether it controls the fate decision of mesenchymal progenitor cells. Our findings indicate that in osteoporotic bones, Ash1l was significantly decreased, indicating a positive correlation between bone mass and the expression of Ash1l. Silencing of Ash1l that had been markedly upregulated in differentiated C3H10T1/2 (C3) cells hampered osteogenesis and chondrogenesis but promoted adipogenesis. Consistently, overexpression of an Ash1l SET domain-containing fragment 3 rather than Ash1lΔN promoted osteogenic and chondrogenic differentiation of C3 cells and simultaneously inhibited adipogenic differentiation. This indicates that the role of Ash1l in regulating the differentiation of C3 cells is linked to its histone methyltransferase activity. Subcutaneous ex vivo transplantation experiments confirmed the role of Ash1l in the promotion of osteogenesis. Further experiments proved that Ash1l can epigenetically affect the expression of essential osteogenic and chondrogenic transcription factors. It exerts this impact via modifications in the enrichment of H3K4me3 on their promoter regions. Considering the promotional action of Ash1l on bone, it could potentially prompt new therapeutic strategy to promote osteogenesis. STEM CELLS 2019; 37:115-127 SIGNIFICANCE STATEMENTThe authors' research first discovered that Ash1l can epigenetically affect the expression of essential osteogenic and chondrogenic transcription factors via modifications in the enrichment of H3K4me3 on their promoter regions. These findings helped to further understand the role of Ash1l in the epigenetic regulation of C3H10T1/2 MSCs differentiation, which also makes it potential therapeutic target of bone diseases. Considering the promotional action of Ash1l on bone, it could potentially prompt new therapeutic strategy to promote osteogenesis.

Control of mesenchymal stem cell biology by histone modifications

“…Intriguingly, both ASH1L and H3K4me3 are present at the transcription start sites (TSSs) of Osx, Runx2 and Sox9, whereas only H3K4me3 is present at the TSS of Pparg. Therefore, silencing of Ash1l downregulates H3K4me3 levels on the Osx and Runx2 promoters but not on the Pparg promoter, consistent with the impact of Ash1l silencing on differentiation [59]. Furthermore, knockdown of KDM2A upregulates SOX2 and NANOG expression by increasing H3K4me3 on the promoters of these genes and thus enhances both adipogenic and chondrogenic differentiation potential in human stem cells from the apical papilla (SCAPs) [60].…”

Senile Osteoporosis: The Involvement of Differentiation and Senescence of Bone Marrow Stromal Cells

“…Further, Shen et al found an increased level of acetylation at H3 and H4 histones near the promoter region of OC gene during osteoblastic differentiation of BMSCs, hence, reported an absolute association between core histone and OC gene expression [98]. Apart from these, nicotinamide phosphoribosyltransferase (Nampt), absent, small, or homeotic disc1 like (Ash1l) and CCAAT/enhancer-binding protein beta (CEBPB) have also been reported to play important roles in augmenting osteogenic differentiation of BMSCs [102][103][104]. MicroRNAs being epigenetic regulators also play their roles during osteogenic differentiation of BMSCs.…”

Epigenetic Regulators of Mesenchymal Stem/Stromal Cell Lineage Determination

“…Both Ash1l and H3K4me3 were upregulated in multipotent mouse C3H10T1/2 cells or human BMSC cells undergoing osteogenic, adipogenic or chondrogenic differentiation [24]. Depletion of Ash1l impaired osteo/chondrogenic differentiation but increased adipogenesis, due to a decrease in Hoxa10, Sox9 gene expression and an activation of PPARγ2 expression [24]. Of note, Ash1l and H3K4me3 were found to be downregulated in murine and human osteoporotic bone samples.…”