title: DNA Methylation Indicates Susceptibility to Isoproterenol-Induced Cardiac Pathology and Is Associated With Chromatin States.
abstract: BACKGROUND
  Only a small portion of the known heritability of cardiovascular diseases, such as heart failure, can be explained based on single-gene mutations. Chromatin structure and regulation provide a substrate through which genetic differences in noncoding regions may affect cellular function and response to disease, but the mechanisms are unknown.
  
  
  OBJECTIVE
  We conducted genome-wide measurements of DNA methylation in different strains of mice that are susceptible and resistant to isoproterenol-induced dysfunction to test the hypothesis that this epigenetic mark may play a causal role in the development of heart failure.
  
  
  RESULTS
  BALB/cJ and BUB/BnJ mice, determined to be susceptible and resistant to isoproterenol-induced heart failure, respectively, were administered the drug for 3 weeks via osmotic minipump. Reduced representational bisulfite sequencing was then used to compare the differences between the cardiac DNA methylomes in the basal state between strains and then after isoproterenol treatment. Single-base resolution DNA methylation measurements were obtained and revealed a bimodal distribution of methylation in the heart, enriched in lone intergenic CpGs and depleted from CpG islands around genes. Isoproterenol induced global decreases in methylation in both strains; however, the basal methylation pattern between strains shows striking differences that may be predictive of disease progression before environmental stress. The global correlation between promoter methylation and gene expression (as measured by microarray) was modest and revealed itself only with focused analyses of transcription start site and gene body regions (in contrast to when gene methylation was examined in toto). Modules of comethylated genes displayed correlation with other protein-based epigenetic marks, supporting the hypothesis that chromatin modifications act in a combinatorial manner to specify transcriptional phenotypes in the heart.
  
  
  CONCLUSIONS
  This study provides the first single-base resolution map of the mammalian cardiac DNA methylome and the first case-control analysis of the changes in DNA methylation with heart failure. The findings demonstrate marked genetic differences in DNA methylation that are associated with disease progression.
authors.affiliation: From the Departments of Anesthesiology and Perioperative Medicine (H.C., C.D.R., S.R., Y.W., T.M.V.), Human Genetics (A.J.L.), Microbiology, Immunology and Molecular Genetics (A.J.L.), Molecular, Cellular and Development Biology (L.D.O., L.R., M.P.), Medicine/Cardiology (J.W., Y.W., A.J.L., T.M.V.), and Physiology, David Geffen School of Medicine, University of California, Los Angeles (Y.W., T.M.V.). hdchen.ucla@gmail.com tvondriska@mednet.ucla.edu.
authors.forename: Haodong
authors.initials: H
authors.lastname: Chen
authors.affiliation: From the Departments of Anesthesiology and Perioperative Medicine (H.C., C.D.R., S.R., Y.W., T.M.V.), Human Genetics (A.J.L.), Microbiology, Immunology and Molecular Genetics (A.J.L.), Molecular, Cellular and Development Biology (L.D.O., L.R., M.P.), Medicine/Cardiology (J.W., Y.W., A.J.L., T.M.V.), and Physiology, David Geffen School of Medicine, University of California, Los Angeles (Y.W., T.M.V.).
authors.forename: Luz D
authors.initials: LD
authors.lastname: Orozco
authors.affiliation: From the Departments of Anesthesiology and Perioperative Medicine (H.C., C.D.R., S.R., Y.W., T.M.V.), Human Genetics (A.J.L.), Microbiology, Immunology and Molecular Genetics (A.J.L.), Molecular, Cellular and Development Biology (L.D.O., L.R., M.P.), Medicine/Cardiology (J.W., Y.W., A.J.L., T.M.V.), and Physiology, David Geffen School of Medicine, University of California, Los Angeles (Y.W., T.M.V.).
authors.forename: Jessica
authors.initials: J
authors.lastname: Wang
authors.affiliation: From the Departments of Anesthesiology and Perioperative Medicine (H.C., C.D.R., S.R., Y.W., T.M.V.), Human Genetics (A.J.L.), Microbiology, Immunology and Molecular Genetics (A.J.L.), Molecular, Cellular and Development Biology (L.D.O., L.R., M.P.), Medicine/Cardiology (J.W., Y.W., A.J.L., T.M.V.), and Physiology, David Geffen School of Medicine, University of California, Los Angeles (Y.W., T.M.V.).
authors.forename: Christoph D
authors.initials: CD
authors.lastname: Rau
authors.affiliation: From the Departments of Anesthesiology and Perioperative Medicine (H.C., C.D.R., S.R., Y.W., T.M.V.), Human Genetics (A.J.L.), Microbiology, Immunology and Molecular Genetics (A.J.L.), Molecular, Cellular and Development Biology (L.D.O., L.R., M.P.), Medicine/Cardiology (J.W., Y.W., A.J.L., T.M.V.), and Physiology, David Geffen School of Medicine, University of California, Los Angeles (Y.W., T.M.V.).
authors.forename: Liudmilla
authors.initials: L
authors.lastname: Rubbi
authors.affiliation: From the Departments of Anesthesiology and Perioperative Medicine (H.C., C.D.R., S.R., Y.W., T.M.V.), Human Genetics (A.J.L.), Microbiology, Immunology and Molecular Genetics (A.J.L.), Molecular, Cellular and Development Biology (L.D.O., L.R., M.P.), Medicine/Cardiology (J.W., Y.W., A.J.L., T.M.V.), and Physiology, David Geffen School of Medicine, University of California, Los Angeles (Y.W., T.M.V.).
authors.forename: Shuxun
authors.initials: S
authors.lastname: Ren
authors.affiliation: From the Departments of Anesthesiology and Perioperative Medicine (H.C., C.D.R., S.R., Y.W., T.M.V.), Human Genetics (A.J.L.), Microbiology, Immunology and Molecular Genetics (A.J.L.), Molecular, Cellular and Development Biology (L.D.O., L.R., M.P.), Medicine/Cardiology (J.W., Y.W., A.J.L., T.M.V.), and Physiology, David Geffen School of Medicine, University of California, Los Angeles (Y.W., T.M.V.).
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Departments of Anesthesiology and Perioperative Medicine (H.C., C.D.R., S.R., Y.W., T.M.V.), Human Genetics (A.J.L.), Microbiology, Immunology and Molecular Genetics (A.J.L.), Molecular, Cellular and Development Biology (L.D.O., L.R., M.P.), Medicine/Cardiology (J.W., Y.W., A.J.L., T.M.V.), and Physiology, David Geffen School of Medicine, University of California, Los Angeles (Y.W., T.M.V.).
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: From the Departments of Anesthesiology and Perioperative Medicine (H.C., C.D.R., S.R., Y.W., T.M.V.), Human Genetics (A.J.L.), Microbiology, Immunology and Molecular Genetics (A.J.L.), Molecular, Cellular and Development Biology (L.D.O., L.R., M.P.), Medicine/Cardiology (J.W., Y.W., A.J.L., T.M.V.), and Physiology, David Geffen School of Medicine, University of California, Los Angeles (Y.W., T.M.V.).
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: From the Departments of Anesthesiology and Perioperative Medicine (H.C., C.D.R., S.R., Y.W., T.M.V.), Human Genetics (A.J.L.), Microbiology, Immunology and Molecular Genetics (A.J.L.), Molecular, Cellular and Development Biology (L.D.O., L.R., M.P.), Medicine/Cardiology (J.W., Y.W., A.J.L., T.M.V.), and Physiology, David Geffen School of Medicine, University of California, Los Angeles (Y.W., T.M.V.). hdchen.ucla@gmail.com tvondriska@mednet.ucla.edu.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Vondriska
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000633:toxicity; D002843:Chromatin / Q000502:physiology*; D018899:CpG Islands / Q000502:physiology; D019175:DNA Methylation / Q000502:physiology*; D004198:Disease Susceptibility; D005260:Female; D006333:Heart Failure / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D007545:Isoproterenol / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D013045:Species Specificity
chemical_list: D002316:Cardiotonic Agents; D002843:Chromatin; D007545:Isoproterenol
keywords: DNA methylation; chromatin; epigenomics; genetics; heart failure
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