Post-transcriptional Regulation of Cardiac and Skeletal Muscle microRNAs

The heart develops and functions through the precise actions of myriad factors at specific moments and in response to signaling and transcriptional networks. MicroRNAs (miRNAs), a class of small, noncoding RNAs, regulate the dosage of such factors and are thus critical contributors to cardiac development and function. The expression of miRNAs, like that of protein-coding genes, is spatially and temporally regulated, and some miRNAs are transcribed only in the heart or vasculature. However, post transcriptional processing is required to generate active, mature, cytoplasmic miRNAs from primary miRNA-encoding transcripts.

We understand the basic molecular events mediating these processing steps, and the biogenesis, stability and even activity of miRNAs can be controlled in a context-dependent manner through interactions with specific factors. This level of gene regulation is a novel area for investigation that could be manipulated to control the cellular activity of miRNAs.

miR-1 is enriched in cardiac and skeletal muscle. Its targeted deletion in mice perturbs
cardiac development and alters adult heart function. In contrast, deletion of other individual miRNAs often results in no overt phenotype. Interestingly, sequencing has revealed that miR-1 comprises ~40% of mature miRNA in cardiac cells, even though hundreds of unique miRNAs are expressed in the heart. This finding suggests that miR-1 is stabilized post-transcriptionally. Finally, unlike most miRNAs, mature miR-1 accumulates in the nucleus, and its function there is entirely unknown.

My laboratory is investigating these unique characteristics of miR-1 with a goal of understanding the unexplored potential of posttranscriptional miRNA regulation, specifically during development and in diseases of cardiac and skeletal muscle. We identified a unique interaction between miR-1 and an RNA-binding protein, mutations of which are associated with a muscle-wasting disease and have the potential to alter the subcellular localization of miR-1. We are investigating the effects of this protein interaction on miR-1 function in normal and diseased heart and skeletal muscle using induced pluripotent stem cell technology to create these cell types from healthy and diseased individuals.