Epitranscriptional orchestration of genetic reprogramming is an emergent property of stress-regulated cardiac microRNAs

Abstract

Cardiac stress responses are driven by an evolutionarily conserved gene expression program comprising dozens of microRNAs and hundreds of mRNAs. Functionalities of different individual microRNAs are being studied, but the overall purpose of interactions between stress-regulated microRNAs and mRNAs and potentially distinct roles for microRNA-mediated epigenetic and conventional transcriptional genetic reprogramming of the stressed heart are unknown. Here we used deep sequencing to interrogate microRNA and mRNA regulation in pressure-overloaded mouse hearts, and performed a genome-wide examination of microRNA-mRNA interactions during early cardiac hypertrophy. Based on abundance and regulatory patterns, cardiac microRNAs were categorized as constitutively expressed housekeeping, regulated homeostatic, or dynamic early stress-responsive microRNAs. Regulation of 62 stressresponsive cardiac microRNAs directly affected levels of only 66 mRNAs, but the global impact of microRNA-mediated epigenetic regulation was amplified by preferential targeting of mRNAs encoding transcription factors, kinases, and phosphatases exerting amplified secondary effects. Thus, an emergent cooperative property of stress-regulated microRNAs is orchestration of transcriptional and posttranslational events that help determine the stress-reactive cardiac phenotype. This global functionality explains how large endorgan effects can be induced through modest individual changes in target mRNA and protein content by microRNAs that sense and respond dynamically to a changing physiological milieu.microRNA-mRNA interactome | transcriptome regulation | systems biology

Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

“…Significantly, a deep sequencing profile of miR expression in mouse heart [124] found that miR 133b is expressed at about 1/6 of the level of miR 133a, reflecting that microarraybased studies may underestimate the relative levels of important miR isomers. Importantly, such deep sequencing analyses also question the canonical view that miR133b is not expressed in cardiac tissue, reinforcing the need to employ sensitive and accurate analysis to extend our understanding of miR involvement in biological processes.…”

Function and Therapeutic Potential of Noncoding RNAs in Cardiac Fibrosis

“…miR-22 is the most abundantly expressed miRNA in the heart. 55 Despite its high expression, this miRNA is dispensable for cardiac development and morphogenesis because the miR-22 knockout mice do not reveal any cardiac abnormalities under basal conditions. However, upon cardiac stress (isoproterenol or TAC), miR-22 knockout mice quickly develop dilated cardiomyopathy accompanied with increased deposition of fibrotic tissue.…”

Great Expectations

“…18 Furthermore, RNA sequencing is inherently quantitative, whereas "spike-in" protocols, such as the one used by Melman et al 6 to normalize quantitative Sequence data are expressed as reads per million aligned microRNA reads. GSE numbers are NCBI Gene Expression Omnibus subseries files for the original sequence data from references 7,8,10 . CM indicates cardiomyopathy; and isch, ischemic.…”

“…Sequence data are expressed as reads per million aligned microRNA reads. GSE numbers are NCBI Gene Expression Omnibus subseries files for the original sequence data from references 7,8,10 . TAC indicates traverse aortic coarctation.…”