Experimental heart failure modelled by the cardiomyocyte-specific loss of an epigenome modifier, DNMT3B

A Vujic, E L Robinson, M Ito, S Haider, M Ackers-Johnson, K See, C Methner, N Figg, P Brien, H L Roderick, J Skepper, A Ferguson-Smith, R S Foo*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Differential DNA methylation exists in the epigenome of end-stage failing human hearts but whether it contributes to disease progression is presently unknown. Here, we report that cardiac specific deletion of Dnmt3b, the predominant DNA methyltransferase in adult mouse hearts, leads to an accelerated progression to severe systolic insufficiency and myocardial thinning without a preceding hypertrophic response. This was accompanied by widespread myocardial interstitial fibrosis and myo-sarcomeric disarray. By targeted candidate gene quantitative RT-PCR, we discovered an over-activity of cryptic splice sites in the sarcomeric gene Myh7, resulting in a transcript with 8 exons missing. Moreover, a region of differential methylation overlies the splice site locus in the hearts of the cardiac-specific conditional knockout (CKO) mice. Although abundant and complex forms of alternative splice variants have been reported in diseased hearts and the contribution of each remains to be understood in further detail, our results demonstrate for the first time that a link may exist between alternative splicing and the cardiac epigenome. In particular, this gives the novel evidence whereby the loss of an epigenome modifier promotes the development and progression of heart disease.

Original languageEnglish
Pages (from-to)174-83
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume82
DOIs
Publication statusPublished - May 2015
Externally publishedYes

Keywords

  • Alternative Splicing
  • Animals
  • DNA (Cytosine-5-)-Methyltransferases/genetics
  • DNA Methylation
  • Disease Models, Animal
  • Epigenesis, Genetic
  • Fibrosis
  • Gene Deletion
  • Gene Expression Regulation
  • Heart Failure/genetics
  • Heart Failure, Systolic/genetics
  • Humans
  • Mice
  • Mice, Knockout
  • Myocardium/metabolism
  • Myocytes, Cardiac/metabolism
  • Myosin Heavy Chains/genetics
  • Organ Specificity/genetics
  • Protein Aggregates
  • Proteolysis
  • Sarcomeres/genetics
  • Ubiquitin/metabolism

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