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

Yuanxin Hu, Scot J. Matkovich, Peter A. Hecker, Yan Zhang, John R. Edwards, Gerald W. Dorn

Research output: Contribution to journalArticle

48 Scopus citations

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 stress-responsive 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.

Original languageEnglish
Pages (from-to)19864-19869
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number48
DOIs
StatePublished - Nov 27 2012

Keywords

  • Systems biology
  • Transcriptome regulation
  • microRNA-mRNA interactome

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