Identification of regulatory elements directing miR-23a–miR-27a–miR-24-2 transcriptional regulation in response to muscle hypertrophic stimuli

Abstract

MiRNAs are small non-coding RNAs that significantly regulate the translation of protein coding genes in higher organisms. MicroRNAs are involved in almost every biological process, including early development, lineage commitment, growth and differentiation, cell death, and metabolic control. Misregulation of miRNAs belonging to the intergenic miR-23a–miR-27a–miR-24-2 cluster has been recently associated to cardiac and skeletal muscle diseases, and they are up-regulated in hypertrophic cardiomyopathy and skeletal muscle atrophy. Despite these facts, the basal transcriptional regulation of miR-23a/miR-27-a/miR-24-2 cluster and how it is altered under pathological conditions remain unclear. In this study, we identified and functionally characterized conserved upstream and downstream regulatory sequences from the miR-23a–miR-27a–miR-24-2 locus that are implicated on its transcriptional control. Our data demonstrate that Srf plays a pivotal role in modulating miR-23a–miR-27a–miR-24-2 cluster proximal promoter activity. Importantly, pro-hypertrophic signalling pathways such as those driven by angiotensin II and norepinephrine also regulate miR-23a–miR-27a–miR-24-2 cluster proximal promoter activity. Taking together, our results provide new insights into the regulatory networks driving miR-23a–miR-27a–miR-24-2 cluster expression in cardiac and skeletal muscles.