title: DNA hydroxymethylation controls cardiomyocyte gene expression in development and hypertrophy.
abstract: Methylation at 5-cytosine (5-mC) is a fundamental epigenetic DNA modification associated recently with cardiac disease. In contrast, the role of 5-hydroxymethylcytosine (5-hmC)-5-mC's oxidation product-in cardiac biology and disease is unknown. Here we assess the hydroxymethylome in embryonic, neonatal, adult and hypertrophic mouse cardiomyocytes, showing that dynamic modulation of hydroxymethylated DNA is associated with specific transcriptional networks during heart development and failure. DNA hydroxymethylation marks the body of highly expressed genes as well as distal regulatory regions with enhanced activity. Moreover, pathological hypertrophy is characterized by a shift towards a neonatal 5-hmC distribution pattern. We also show that the ten-eleven translocation 2 (TET2) enzyme regulates the expression of key cardiac genes, such as Myh7, through 5-hmC deposition on the gene body and at enhancers. Thus, we provide a genome-wide analysis of 5-hmC in the cardiomyocyte and suggest a role for this epigenetic modification in heart development and disease.
authors.affiliation: Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano (MI) 20089, Italy.
authors.forename: Carolina M
authors.identifier: 0000-0002-9895-5635
authors.initials: CM
authors.lastname: Greco
authors.affiliation: Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano (MI) 20089, Italy.
authors.forename: Paolo
authors.identifier: 0000-0003-3636-3391
authors.initials: P
authors.lastname: Kunderfranco
authors.affiliation: Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano (MI) 20089, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Rubino
authors.affiliation: Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano (MI) 20089, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Larcher
authors.affiliation: Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano (MI) 20089, Italy.|Institute of Genetics and Biomedical Research, National Research Council of Italy, Via Manzoni 56, Rozzano (MI) 20089, Italy.
authors.forename: Pierluigi
authors.identifier: 0000-0003-0812-7770
authors.initials: P
authors.lastname: Carullo
authors.affiliation: Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano (MI) 20089, Italy.
authors.forename: Achille
authors.initials: A
authors.lastname: Anselmo
authors.affiliation: Center for Integrated Protein Science, Department of Chemistry, Ludwig-Maximilians-Universität München, 8137 Munich, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kurz
authors.affiliation: Center for Integrated Protein Science, Department of Chemistry, Ludwig-Maximilians-Universität München, 8137 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Carell
authors.affiliation: Institute of Genetics and Biomedical Research, National Research Council of Italy, Via Manzoni 56, Rozzano (MI) 20089, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Angius
authors.affiliation: Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano (MI) 20089, Italy.
authors.forename: Michael V G
authors.initials: MV
authors.lastname: Latronico
authors.affiliation: Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano (MI) 20089, Italy.|Institute of Genetics and Biomedical Research, National Research Council of Italy, Via Manzoni 56, Rozzano (MI) 20089, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Papait
authors.affiliation: Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano (MI) 20089, Italy.|Institute of Genetics and Biomedical Research, National Research Council of Italy, Via Manzoni 56, Rozzano (MI) 20089, Italy.|Humanitas University, Via Manzoni 56, Rozzano (MI) 20089, Italy.|Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK.
authors.forename: Gianluigi
authors.identifier: 0000-0003-0481-6843
authors.initials: G
authors.lastname: Condorelli
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D049308:Dioxygenases; D004742:Enhancer Elements, Genetic / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D016678:Genome; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D049308:Dioxygenases; C551914:Tet2 protein, mouse