The Mef2 transcription network is disrupted in myotonic dystrophy heart tissue, dramatically altering miRNA and mRNA expression. Cell Rep 2014 Jan 30;6(2):336-45
Date
01/15/2014Pubmed ID
24412363Pubmed Central ID
PMC3927417DOI
10.1016/j.celrep.2013.12.025Scopus ID
2-s2.0-84895907629 (requires institutional sign-in at Scopus site) 74 CitationsAbstract
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.
Author List
Kalsotra A, Singh RK, Gurha P, Ward AJ, Creighton CJ, Cooper TAMESH terms used to index this publication - Major topics in bold
AdultAnimals
Case-Control Studies
Female
Gene Regulatory Networks
Humans
MEF2 Transcription Factors
Male
Mice
MicroRNAs
Middle Aged
Myocardium
Myotonic Dystrophy
RNA, Messenger