Mohammad Q Hassan
University of Alabama, USA
Title: A Network Connecting miR-23a cluster and HOXA Class Factors Regulate Osteogenesis
Biography
Biography: Mohammad Q Hassan
Abstract
Studies of HOXA class genes have indicated their importance in skeletogenesis, but their regulation by specific miRNA in bone formation and homeostasis are incompletely defined. MiRNA regulation contributes to every step of osteogenesis, including differentiation, skeletal patterning, and homeostasis. We recently identified miRNA-23a cluster as a potential repressor of osteoblast maturation by targeting Runx2 and Satb2. In our study there is very strong evidence that miR-23a cluster is likely to regulate osteogenesis. Here we have established a mechanism where miR-23a cluster silenced Hoxa5, Hoxa10 and Hoxa11-mediated gene activation, and also identified epigenetic changes associated with poor maturation and mineralization of osteoblasts. Among 11 HOXA class proteins, miR-23a cluster directly targeted Hoxa5, Hoxa10 and Hoxa11 and decreased their expression. HOXA5, HOXA10 and HOXA11 are all interacted physically and functionally with RUNX2, to regulate tissue-specific promoter activity. Overexpression of miR-23a cluster reduced while knockdown increased the recruitment of HOXA5, HOXA10 and HOXA11 to Runx2, Ocn, and Alp promoters and epigenetically control HOXA5 and HOXA11-facilitated chromatin remodeling. Targeted depletion of HoxA5 and HoxA11 by short hairpin RNA (shRNA) decreased expression of osteoblast-related genes while increased SIBLING protein osteopontin. Taken together, our results provide novel molecular evidence that miR-23a cluster and target HOXA5 and A11 functions in an miRNA-epigenetic regulatory network to control osteogenesis. Therefore, the analysis of this miR-23a cluster knockdown mouse model and supportive epigenetic changes by HOXA5, HOXA10 and HOXA11 will dramatically enrich our understanding of this newly recognized level of gene regulation in bone formation.