Novel insights into the regulation of miRNA transcriptional control: implications for T2D and related complications

In recent years, epigenetics has emerged as an important form of biological regulation involving chromatin control of gene expression. The mechanisms of this fine-tuned regulation are susceptible to changes forced by environmental stimuli and nutritional factors and may be potentially reversible. Dysregulation of epigenetic processes has important consequences for the pathogenesis of complex and multifactorial diseases such as type 2 diabetes (T2D) and vascular complications. Along with DNA methylation (DNA-me), histone modifications and RNA-based mechanisms as the major epigenetic controllers, small non-coding RNAs known as microRNAs (miRNAs) have their own important implications for the pathogenesis of diabetes. There is increasing evidence supporting the role of miRNAs in modulating gene expression, cumulatively contributing to epigenetic gene silencing by acting either on the methylation status of the cells or in alternative roles. Although significant progress has been made in the characterization of miRNA functions, most miRNA promoters have not yet been characterized, and the transcriptional regulation of miRNAs remains elusive. The present work is centred on the new biological insights pertaining to the epigenetics–miRNA regulatory axis, focusing on the development of T2D and cardiovascular complications, and the ability of these mechanisms to interact in a network of DNA-me regulation. The genomic organization of inter- and intragenic miRNA genes is discussed, and the mutual connections between pre-mRNA splicing and miRNA biogenesis are summarized, along with the discovery of novel miRNA transcriptional regulation sites.