Epigenetic remodeling and modification to preserve skeletogenesis in vivo

Abstract

Current studies offer little insight on how epigenetic remodeling of bone-specific chromatin maintains bone mass in vivo. Understanding this gap and precise mechanism is pivotal for future therapeutic innovation to prevent bone loss. Recently, we found that low bone mass is associated with decreased H3K27 acetylation (activating histone modification) of bone specific gene promoters. Here, we aim to elucidate the epigenetic mechanisms by which a miRNA cluster controls bone synthesis and homeostasis by regulating chromatin accessibility and H3K27 acetylation. In order to decipher the epigenetic axis that regulates osteogenesis, we studied a drug inducible anti-miR-23a cluster (miR-23a ClZIP) knockdown mouse model. MiR-23a cluster knockdown (heterozygous) mice developed high bone mass. These mice displayed increased expression of Runx2 and Baf45a, essential factors for skeletogenesis; and decreased expression of Ezh2, a chromatin repressor indispensable for skeletogenesis. ChIP assays using miR-23a Cl knockdown calvarial cells revealed a BAF45A-EZH2 epigenetic antagonistic mechanism that maintains bone formation. Together, our findings support that the miR-23a Cl connection with tissue-specific RUNX2-BAF45A-EZH2 function is a novel molecular epigenetic axis through which a miRNA cluster orchestrates chromatin modification to elicit major effects on osteogenesis in vivo.

Baf45a Mediated Chromatin Remodeling Promotes Transcriptional Activation for Osteogenesis and Odontogenesis

“…Increased Histone H3K9 and H3K27 Acetylation and RUNX2 Occupancy Indicate Baf45a and Baf45d Promoters Are Highly Accessible During Induction of BMSCs to Osteoblast Differentiation Studies previously suggested that Baf45a associated chromatin remodeling facilitates neurogenic differentiation (28). We currently identified that Baf45a remodeled chromatin implicate the transcriptional activation of osteoblast-specific genes (37). Lately, we found that osteoblast-specific deletion of Baf45a reduced bone formation in vivo.…”

“…Studies previously suggested that Baf45a associated chromatin remodeling facilitates neurogenic differentiation ( 28 ). We currently identified that Baf45a remodeled chromatin implicate the transcriptional activation of osteoblast-specific genes ( 37 ). Lately, we found that osteoblast-specific deletion of Baf45a reduced bone formation in vivo .…”

“…Much of what we know about the regulation of this gene program comes from our understanding of the bone gene transcriptional program and bonetissue-specific signaling (30,31). Furthermore, growing studies about the epigenetic regulation involved in osteogenesis primarily focus on histone post-translational modifications, miRNA, and non-coding RNAs (32)(33)(34)(35)(36)(37)(38)(39). However, the tissue-specific mechanisms involved in the openness of the chromatin around active genes are understudied in osteogenesis.…”

“…Our lab’s recent preliminary findings have demonstrated that the PBAF subunit BAF45A is preserving epigenetic balance for osteogenesis ( 37 ). There are four BAF45 homologs, Baf45(a-d) .…”

Histone modifications centric-regulation in osteogenic differentiation

“…In a study performed to evaluate the epigenetic mechanisms of miR-23a in regulating bone synthesis and homeostasis, knockdown of the miR-23a cluster was shown to enhance osteogenic differentiation with decreased expression of EZH2 and increased expression of Baf45a, a factor responsible for increasing chromatin accessibility. This resulted in the induction of OC by increasing H3K27ac levels and decreasing H3K27me3 levels at the OC gene promoter 77 .…”