The Mef2 Transcription Network Is Disrupted in Myotonic Dystrophy Heart Tissue, Dramatically Altering miRNA and mRNA Expression

• Published in: Cell reports (Cambridge) Vol. 6; no. 2; pp. 336 - 345
• Main Authors: Kalsotra, Auinash, Singh, Ravi K., Gurha, Priyatansh, Ward, Amanda J., Creighton, Chad J., Cooper, Thomas A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2014; Elsevier
• Subjects: Adult; Animals; Case-Control Studies; Female; Gene Regulatory Networks; Humans; Male; MEF2 Transcription Factors - genetics; MEF2 Transcription Factors - metabolism; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; Myocardium - metabolism; Myocardium - pathology; Myotonic Dystrophy - genetics; Myotonic Dystrophy - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.12.025

Cardiac dysfunction is the second leading cause of death in myotonic dystrophy type 1 (DM1), primarily because of arrhythmias and cardiac conduction defects. A screen of more than 500 microRNAs (miRNAs) in a DM1 mouse model identified 54 miRNAs that were differentially expressed in heart. More than 80% exhibited downregulation toward the embryonic expression pattern and showed a DM1-specific response. A total of 20 of 22 miRNAs tested were also significantly downregulated in human DM1 heart tissue. We demonstrate that many of these miRNAs are direct MEF2 transcriptional targets, including miRNAs for which depletion is associated with arrhythmias or fibrosis. MEF2 protein is significantly reduced in both DM1 and mouse model heart samples, and exogenous MEF2C restores normal levels of MEF2 target miRNAs and mRNAs in a DM1 cardiac cell culture model. We conclude that loss of MEF2 in DM1 heart causes pathogenic features through aberrant expression of both miRNA and mRNA targets. [Display omitted] •The MEF2 regulatory network is disrupted in DM1 cardiac tissue•Altered expression is specific to DM1 and not a general response to cardiac injury•Multiple miRNA genes identified as MEF2 targets in postnatal heart development•miRNA expression is rescued by MEF2C expression in a DM1 cardiomyocyte model Myotonic dystrophy type 1 (DM1) is caused by the expression of an RNA containing an expanded CUG repeat. The best-characterized pathogenic effects are through disruption of alternative splicing and microRNA expression. Cooper and colleagues demonstrate that the MEF2 transcription factor is downregulated in heart tissue from DM1 patients and a DM1 mouse model. The results identify microRNA targets of MEF2 that are downregulated in DM1 tissue and reveal that transcriptional as well as posttranscriptional events are disrupted.