Dynamic DNA Methylation Orchestrates Cardiomyocyte Development, Maturation and Disease

Overview

Journal Nat Commun

Specialty Biology

Date 2014 Oct 23

PMID 25335909

Citations 158

Authors

Ralf Gilsbach

Sebastian Preissl

Bjorn A Gruning

Tilman Schnick

Lukas Burger

Vladimir Benes

Andreas Wurch

Ulrike Bonisch

Stefan Gunther

Rolf Backofen

Bernd K Fleischmann

Dirk Schubeler

Lutz Hein

Affiliations

Soon will be listed here.

Abstract

The heart is a highly specialized organ with essential function for the organism throughout life. The significance of DNA methylation in shaping the phenotype of the heart remains only partially known. Here we generate and analyse DNA methylomes from highly purified cardiomyocytes of neonatal, adult healthy and adult failing hearts. We identify large genomic regions that are differentially methylated during cardiomyocyte development and maturation. Demethylation of cardiomyocyte gene bodies correlates strongly with increased gene expression. Silencing of demethylated genes is characterized by the polycomb mark H3K27me3 or by DNA methylation. De novo methylation by DNA methyltransferases 3A/B causes repression of fetal cardiac genes, including essential components of the cardiac sarcomere. Failing cardiomyocytes partially resemble neonatal methylation patterns. This study establishes DNA methylation as a highly dynamic process during postnatal growth of cardiomyocytes and their adaptation to pathological stress in a process tightly linked to gene regulation and activity.

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References

Haas J, Frese K, Park Y, Keller A, Vogel B, Lindroth A . Alterations in cardiac DNA methylation in human dilated cardiomyopathy. EMBO Mol Med. 2013; 5(3):413-29. PMC: 3598081. DOI: 10.1002/emmm.201201553. View

Senyo S, Steinhauser M, Pizzimenti C, Yang V, Cai L, Wang M . Mammalian heart renewal by pre-existing cardiomyocytes. Nature. 2012; 493(7432):433-6. PMC: 3548046. DOI: 10.1038/nature11682. View

Taegtmeyer H, Sen S, Vela D . Return to the fetal gene program: a suggested metabolic link to gene expression in the heart. Ann N Y Acad Sci. 2010; 1188:191-8. PMC: 3625436. DOI: 10.1111/j.1749-6632.2009.05100.x. View

Ehler E, Moore-Morris T, Lange S . Isolation and culture of neonatal mouse cardiomyocytes. J Vis Exp. 2013; (79). PMC: 3857885. DOI: 10.3791/50154. View

Bergmann O, Bhardwaj R, Bernard S, Zdunek S, Barnabe-Heider F, Walsh S . Evidence for cardiomyocyte renewal in humans. Science. 2009; 324(5923):98-102. PMC: 2991140. DOI: 10.1126/science.1164680. View

Okano M, BELL D, Haber D, Li E . DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999; 99(3):247-57. DOI: 10.1016/s0092-8674(00)81656-6. View

Heinz S, Benner C, Spann N, Bertolino E, Lin Y, Laslo P . Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010; 38(4):576-89. PMC: 2898526. DOI: 10.1016/j.molcel.2010.05.004. View

Srivastava D . Making or breaking the heart: from lineage determination to morphogenesis. Cell. 2006; 126(6):1037-48. DOI: 10.1016/j.cell.2006.09.003. View

Xie W, Schultz M, Lister R, Hou Z, Rajagopal N, Ray P . Epigenomic analysis of multilineage differentiation of human embryonic stem cells. Cell. 2013; 153(5):1134-48. PMC: 3786220. DOI: 10.1016/j.cell.2013.04.022. View

10.

Branco M, Ficz G, Reik W . Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nat Rev Genet. 2011; 13(1):7-13. DOI: 10.1038/nrg3080. View

11.

Ziller M, Gu H, Muller F, Donaghey J, Tsai L, Kohlbacher O . Charting a dynamic DNA methylation landscape of the human genome. Nature. 2013; 500(7463):477-81. PMC: 3821869. DOI: 10.1038/nature12433. View

12.

Grueter C, Van Rooij E, Johnson B, DeLeon S, Sutherland L, Qi X . A cardiac microRNA governs systemic energy homeostasis by regulation of MED13. Cell. 2012; 149(3):671-83. PMC: 3340581. DOI: 10.1016/j.cell.2012.03.029. View

13.

Zhuang S, Zhang Q, Zhuang T, Evans S, Liang X, Sun Y . Expression of Isl1 during mouse development. Gene Expr Patterns. 2013; 13(8):407-12. PMC: 4134129. DOI: 10.1016/j.gep.2013.07.001. View

14.

Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A . ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009; 25(8):1091-3. PMC: 2666812. DOI: 10.1093/bioinformatics/btp101. View

15.

Walsh S, Ponten A, Fleischmann B, Jovinge S . Cardiomyocyte cell cycle control and growth estimation in vivo--an analysis based on cardiomyocyte nuclei. Cardiovasc Res. 2010; 86(3):365-73. DOI: 10.1093/cvr/cvq005. View

16.

Creyghton M, Cheng A, Welstead G, Kooistra T, Carey B, Steine E . Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010; 107(50):21931-6. PMC: 3003124. DOI: 10.1073/pnas.1016071107. View

17.

Langmead B, Trapnell C, Pop M, Salzberg S . Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009; 10(3):R25. PMC: 2690996. DOI: 10.1186/gb-2009-10-3-r25. View

18.

Gilsbach R, Schneider J, Lother A, Schickinger S, Leemhuis J, Hein L . Sympathetic alpha(2)-adrenoceptors prevent cardiac hypertrophy and fibrosis in mice at baseline but not after chronic pressure overload. Cardiovasc Res. 2010; 86(3):432-42. DOI: 10.1093/cvr/cvq014. View

19.

Trapnell C, Williams B, Pertea G, Mortazavi A, Kwan G, van Baren M . Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010; 28(5):511-5. PMC: 3146043. DOI: 10.1038/nbt.1621. View

20.

Royo J, Hidalgo M, Ruiz A . Pyrosequencing protocol using a universal biotinylated primer for mutation detection and SNP genotyping. Nat Protoc. 2007; 2(7):1734-9. DOI: 10.1038/nprot.2007.244. View