Abstract 100: An Altered Epigenomic Mark Predisposes to Dilated Cardiomyopathy Through Alternative Splicing of Sarcomeric Gene Expression in Mice
Distinct epigenomic patterns of DNA methylation exist in important elements of the cardiac genome in human end-stage cardiomyopathy but whether these contribute to disease progression is unknown. We examined and found that the main DNA methyltransferase expressed in the adult mammalian heart is DNMT3B. We therefore generated a conditional inducible Dnmt3b knockout mouse to test the effect of altered DNA methylation in the heart. Upon induction in the adult mouse, Dnmt3b knockout (CKO) led rapidly to severe systolic insufficiency and myocardial thinning. Examination of myocyte nuclei reflected a loss of homogeniety and re-distribution of heterochromatin. This was accompanied by widespread myocardial interstitial fibrosis and myofibrillary disarray. We examined the myocardial transcriptome of CKO mice by RNA-seq and discovered significant changes in levels of transcript splicing isoforms especially those of sarcomeric genes. When subjected to pressure overload, CKO mice failed to mount a compensatory hypertrophic response and instead developed accelerated fulminant dilated cardiomyopathy. Our results demonstrate that DNA methylation has a distinct role with regulating transcript isoform splicing apart from gene expression. In particular, we have highlighted a mechanism by which the epigenome may mediate the development and progression of a complex disease.
- © 2012 by American Heart Association, Inc.