Enhancer of Zeste Homolog 2 and Histone Deacetylase 9c Regulate Age-Dependent Mesenchymal Stem Cell Differentiation into Osteoblasts and Adipocytes

Abstract

Mesenchymal stem cells (MSCs) are multipotent precursors that can undergo multilineage differentiation, including osteogenesis and adipogenesis, which are two mutually exclusive events. Previously, we demonstrated that enhancer of zeste homolog 2 (EZH2), the catalytic component of the Polycomb-repressive complex 2, mediates epigenetic silencing of histone deacetylase 9c (HDAC9c) in adipocytes but not in osteoblasts and that HDAC9c accelerates osteogenesis while attenuating adipogenesis of MSCs through inactivation of peroxisome proliferator-activated receptor gamma 2 activity. Importantly, disrupting the balance between adipogenesis and osteogenesis can lead to age-associated bone loss (osteoporosis) and obesity. Here, we investigated the relationship between age, and osteogenic and adipogenic differentiation potential of MSCs by comparing EZH2 and HDAC9c expression in osteoblasts and adipocytes of both human and mice origins to determine whether the EZH2-HDAC9c axis regulates age-associated osteoporosis and obesity. Our findings indicated that a decline in HDAC9c expression over time was accompanied by increased EZH2 expression and suggested that a therapeutic intervention for age-associated osteoporosis and obesity may be feasible by targeting the EZH2-HDAC9c axis.

Impaired autophagy triggered by HDAC9 in mesenchymal stem cells accelerates bone mass loss

“…Inhibition of HDAC9 by siRNA transfection improved the lineage differentiation capacity and decreased the senescence of aged BMMSCs, whereas HDAC9 inhibition in young BMMSCs not displayed as effective as in aged BMMSCs, possibly because the level of HDAC9 expression was relatively low in young BMMSCs. Interestingly, some studies reported that HDAC9 regulates the osteogenic differentiation of MSCs [33,34]. Chen et al showed that HDAC9 expression decreased in old mice and this was associated with bone aging [34], which contradicts our observations in aged mice.…”

Hedgehog Signaling Overcomes an EZH2-Dependent Epigenetic Barrier to Promote Cholangiocyte Expansion

“…EZH2: -1.2 fold, PCAF: +4.8 fold, P300: +1.9 fold). We subsequently focused on studying the role of EZH2, a key writer of the histone code that enzymatically mediates the H3K27Me3 repressive mark and, in several contexts, antagonizes cell differentiation by acting as an epigenetic barrier[37–39]. We hypothesized, that if functional under the conditions studied here, EZH2 can work as a barrier to cholangiocyte differentiation.…”

Epigenetic‐Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease

“…) . Interestingly, the EZH2‐HDAC9c‐axis has also been recently implicated in age‐dependent osteogenic and adipogenic differentiation of BMSCs . These experiments demonstrated that EZH2 expression increased with aging of primary mouse and human BMSCs, thereby increasing expression of PPARγ and allowing progression of adipogenesis.…”

“…These experiments demonstrated that EZH2 expression increased with aging of primary mouse and human BMSCs, thereby increasing expression of PPARγ and allowing progression of adipogenesis. Inhibition of EZH2 reduced adipogenic differentiation of aged BMSCs and rescued their capacity for osteogenic differentiation . Jing and colleagues reported that elevated EZH2 expression in BMSCs correlated with increased H3K27me3 levels on the Wnt1, Wnt6, and Wnt10a promoters and resulted in their commitment to adipocyte differentiation with osteoporosis.…”