title: Experimental heart failure modelled by the cardiomyocyte-specific loss of an epigenome modifier, DNMT3B.
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.
authors.affiliation: Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation Building, University of Cambridge, Cambridge CB2 0QQ, UK; Cardiovascular Research Institute, Centre for Translational Medicine MD6, National University Health System, 117599 Singapore.
authors.forename: A
authors.initials: A
authors.lastname: Vujic
authors.affiliation: Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation Building, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: E L
authors.initials: EL
authors.lastname: Robinson
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
authors.forename: M
authors.initials: M
authors.lastname: Ito
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, London EC1M 6BQ, UK.
authors.forename: S
authors.initials: S
authors.lastname: Haider
authors.affiliation: Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation Building, University of Cambridge, Cambridge CB2 0QQ, UK; Cardiovascular Research Institute, Centre for Translational Medicine MD6, National University Health System, 117599 Singapore; Genome Institute of Singapore, 60 Biopolis Street, 138672 Singapore.
authors.forename: M
authors.initials: M
authors.lastname: Ackers-Johnson
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, 138672 Singapore.
authors.forename: K
authors.initials: K
authors.lastname: See
authors.affiliation: Clinical Pharmacology Unit, Addenbrooke's Centre for Clinical Investigation Building, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: C
authors.initials: C
authors.lastname: Methner
authors.affiliation: Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation Building, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: N
authors.initials: N
authors.lastname: Figg
authors.affiliation: Epigenetics ISP, Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: P
authors.initials: P
authors.lastname: Brien
authors.affiliation: Epigenetics ISP, Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: H L
authors.initials: HL
authors.lastname: Roderick
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
authors.forename: J
authors.initials: J
authors.lastname: Skepper
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
authors.lastname: A Ferguson-Smith
authors.affiliation: Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation Building, University of Cambridge, Cambridge CB2 0QQ, UK; Cardiovascular Research Institute, Centre for Translational Medicine MD6, National University Health System, 117599 Singapore; Genome Institute of Singapore, 60 Biopolis Street, 138672 Singapore. Electronic address: mdcrfsy@nus.edu.sg.
authors.forename: R S
authors.initials: RS
authors.lastname: Foo
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005355:Fibrosis; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D054143:Heart Failure, Systolic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics; D009928:Organ Specificity / Q000235:genetics; D066329:Protein Aggregates; D059748:Proteolysis; D012518:Sarcomeres / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025801:Ubiquitin / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D018995:Myosin Heavy Chains; D066329:Protein Aggregates; D025801:Ubiquitin; D000097584:DNA Methyltransferase 3B
keywords: Alternative splicing; DNA methylation; Epigenome; Heart failure