Histone Methylation in Heart Development and Cardiovascular Disease

  • Zhi-Ping LiuEmail author
Part of the Cardiac and Vascular Biology book series (Abbreviated title: Card. vasc. biol.)


Cardiovascular development and homeostasis are regulated by a group of core cardiac transcription factors in a coordinated temporal and spatial manner. Histone methylation is an emerging epigenetic mechanism for regulating gene transcription. Interplay among transcription factors and histone lysine modifiers plays important role in cardiovascular development and diseases. Aberrant expression and mutation of the histone lysine modifiers during development and in adult life can cause either embryonic lethality or congenital heart diseases, and influences the response of adult hearts to pathological stresses. In this review, we describe basics of histone methylation, and current body of literature on the role of several common histone methylations and their modifying enzymes in cardiovascular development, congenital and adult heart diseases.


Congenital Heart Disease Histone Methylation Hypoplastic Left Heart Syndrome H3K4 Methylation Heart Development 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Conflict of Interest

The authors declare that they have no conflict of interest.


  1. Abu-Farha M, Lambert JP, Al-Madhoun AS et al (2008) The tale of two domains: proteomics and genomics analysis of SMYD2, a new histone methyltransferase. Mol Cell Proteomics 7(3):560–572CrossRefPubMedGoogle Scholar
  2. Alabert C, Groth A (2012) Chromatin replication and epigenome maintenance. Nat Rev Mol Cell Biol 13(3):153–167CrossRefPubMedGoogle Scholar
  3. Allfrey VG, Faulkner R, Mirsky AE (1964) Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc Natl Acad Sci U S A 51:786–794CrossRefPubMedPubMedCentralGoogle Scholar
  4. Aramaki M, Udaka T, Kosaki R et al (2006) Phenotypic spectrum of CHARGE syndrome with CHD7 mutations. J Pediatr 148(3):410–414CrossRefPubMedGoogle Scholar
  5. Bannister AJ, Zegerman P, Partridge JF et al (2001) Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410(6824):120–124CrossRefPubMedGoogle Scholar
  6. Barker DJ (1999) Fetal origins of cardiovascular disease. Ann Med 1:3–6Google Scholar
  7. Bernstein BE, Mikkelsen TS, Xie X et al (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125(2):315–326CrossRefPubMedGoogle Scholar
  8. Bilodeau S, Kagey MH, Frampton GM et al (2009) SetDB1 contributes to repression of genes encoding developmental regulators and maintenance of ES cell state. Genes Dev 23:2484–2489CrossRefPubMedPubMedCentralGoogle Scholar
  9. Black JC, Whetstine JR (2013) Tipping the lysine methylation balance in disease. Biopolymers 99(2):127–135CrossRefPubMedGoogle Scholar
  10. Bokinni Y (2012) Kabuki syndrome revisited. J Hum Genet 57(4):223–227CrossRefPubMedGoogle Scholar
  11. Brown MA, Sims RJ 3rd, Gottlieb PD et al (2006) Identification and characterization of Smyd2: a split SET/MYND domain-containing histone H3 lysine 36-specific methyltransferase that interacts with the Sin3 histone deacetylase complex. Mol Cancer 5:26CrossRefPubMedPubMedCentralGoogle Scholar
  12. Bruneau BG (2013) Signaling and transcriptional networks in heart development and regeneration. Cold Spring Harb Perspect Biol 5(3):a008292CrossRefPubMedPubMedCentralGoogle Scholar
  13. Caprio C, Baldini A (2014) p53 suppression partially rescues the mutant phenotype in mouse models of DiGeorge syndrome. Proc Natl Acad Sci U S A 111(37):13385–13390CrossRefPubMedPubMedCentralGoogle Scholar
  14. Carrozza MJ, Li B, Florens L et al (2005) Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell 123:581–592CrossRefPubMedGoogle Scholar
  15. Cattaneo P, Kunderfranco P, Greco C et al. (2014) DOT1L-mediated H3K79me2 modification critically regulates gene expression during cardiomyocyte differentiation. Cell Death Differ. doi: 10.1038/cdd.2014.199
  16. Delgado-Olguín P, Huang Y, Li X et al (2012) Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis. Nat Genet 44(3):343–347CrossRefPubMedPubMedCentralGoogle Scholar
  17. Diehl F, Brown MA, van Amerongen MJ et al (2010) Cardiac deletion of Smyd2 is dispensable for mouse heart development. PLoS One 5(3):e9748CrossRefPubMedPubMedCentralGoogle Scholar
  18. Dillon SC, Zhang X, Trievel RC, Cheng X (2005) The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol 6(8):227CrossRefPubMedPubMedCentralGoogle Scholar
  19. Dolinoy DC, Huang D, Jirtle RL (2007) Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci U S A 104(32):13056–13061CrossRefPubMedPubMedCentralGoogle Scholar
  20. Dominguez-Salas P, Cox SE, Prentice AM et al (2012) Maternal nutritional status, C(1) metabolism and offspring DNA methylation: a review of current evidence in human subjects. Proc Nutr Soc 71(1):154–165CrossRefPubMedGoogle Scholar
  21. Fahed AC, Gelb BD, Seidman JG, Seidman CE (2013) Genetics of congenital heart disease: the glass half empty. Circ Res 112:707–720CrossRefPubMedGoogle Scholar
  22. Fish JE, Yan MS, Matouk CC et al (2010) Hypoxic repression of endothelial nitric-oxide synthase transcription is coupled with eviction of promoter histones. J Biol Chem 285:810–826CrossRefPubMedGoogle Scholar
  23. Fujii T, Tsunesumi S, Yamaguchi K et al (2011) Smyd3 is required for the development of cardiac and skeletal muscle in zebrafish. PLoS One 6(8):e23491CrossRefPubMedPubMedCentralGoogle Scholar
  24. Glaser S, Schaft J, Lubitz S et al (2006) Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development. Development 133(8):1423–1432CrossRefPubMedGoogle Scholar
  25. Glaser S, Lubitz S, Loveland KL et al (2009) The histone 3 lysine 4 methyltransferase, Mll2, is only required briefly in development and spermatogenesis. Epigenetics Chromatin 2(1):5. doi: 10.1186/1756-8935-2-5 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Goldsworthy M, Absalom NL, Schröter D et al (2013) Mutations in Mll2, an H3K4 methyltransferase, result in insulin resistance and impaired glucose tolerance in mice. PLoS One 8(6):e61870CrossRefPubMedPubMedCentralGoogle Scholar
  27. Gottlieb PD, Pierce SA, Sims RJ et al (2002) Bop encodes a muscle-restricted protein containing MYND and SET domains and is essential for cardiac differentiation and morphogenesis. Nat Genet 31(1):25–32PubMedGoogle Scholar
  28. Guay SP, Brisson D, Lamarche B et al (2014) ADRB3 gene promoter DNA methylation in blood and visceral adipose tissue is associated with metabolic disturbances in men. Epigenomics 6(1):33–43CrossRefPubMedGoogle Scholar
  29. Hamamoto R, Furukawa Y, Morita M et al (2004) SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat Cell Biol 6(8):731–740CrossRefPubMedGoogle Scholar
  30. Han P, Hang CT, Yang J, Chang CP (2011) Chromatin remodeling in cardiovascular development and physiology. Circ Res 108(3):378–396CrossRefPubMedPubMedCentralGoogle Scholar
  31. He A, Ma Q, Cao J et al (2012) Polycomb repressive complex 2 regulates normal development of the mouse heart. Circ Res 110(3):406–415CrossRefPubMedGoogle Scholar
  32. Heijmans BT, Tobi EW, Stein AD et al (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A 105(44):17046–17049CrossRefPubMedPubMedCentralGoogle Scholar
  33. Hill JA, Olson EN (2008) Cardiac plasticity. N Engl J Med 358(13):1370–1380CrossRefPubMedGoogle Scholar
  34. Ho JJ, Man HS, Marsden PA (2012) Nitric oxide signaling in hypoxia. J Mol Med (Berl) 90(3):217–231CrossRefGoogle Scholar
  35. Hu M, Sun XJ, Zhang YL et al (2010) Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling. Proc Natl Acad Sci U S A 107(7):2956–2961CrossRefPubMedPubMedCentralGoogle Scholar
  36. Just S, Meder B, Berger IM et al (2011) The myosin-interacting protein SMYD1 is essential for sarcomere organization. J Cell Sci 124(Pt 18):3127–3136CrossRefPubMedGoogle Scholar
  37. Kaelin WG Jr, McKnight SL (2013) Influence of metabolism on epigenetics and disease. Cell 153(1):56–69CrossRefPubMedPubMedCentralGoogle Scholar
  38. Kaneda R, Takada S, Yamashita Y et al (2009) Genome-wide histone methylation profile for heart failure. Genes Cells 14(1):69–77CrossRefPubMedGoogle Scholar
  39. Kim D, Patel SR, Xiao H, Dressler GR (2009) The role of PTIP in maintaining embryonic stem cell pluripotency. Stem Cells 27(7):1516–1523CrossRefPubMedPubMedCentralGoogle Scholar
  40. Klose RJ, Kallin EM, Zhang Y (2006) JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet 7(9):715–727CrossRefPubMedGoogle Scholar
  41. Kobayashi J, Yoshida M, Tarui S et al (2014) Directed differentiation of patient-specific induced pluripotent stem cells identifies the transcriptional repression and epigenetic modification of NKX2-5, HAND1, and NOTCH1 in hypoplastic left heart syndrome. PLoS One 9(7):e102796CrossRefPubMedPubMedCentralGoogle Scholar
  42. Krauss V (2008) Glimpses of evolution: heterochromatic histone H3K9 methyltransferases left its marks behind. Genetica 133(1):93–106CrossRefPubMedGoogle Scholar
  43. Lachner M, O'Carroll D, Rea S et al (2001) Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410(6824):116–120CrossRefPubMedGoogle Scholar
  44. Lai HL, Grachoff M, McGinley AL et al (2012) Maintenance of adult cardiac function requires the chromatin factor Asxl2. J Mol Cell Cardiol 53(5):734–741CrossRefPubMedPubMedCentralGoogle Scholar
  45. Lee S, Lee JW, Lee SK (2012) UTX, a histone H3-lysine 27 demethylase, acts as a critical switch to activate the cardiac developmental program. Dev Cell 22(1):25–37CrossRefPubMedGoogle Scholar
  46. Lui JC, Chen W, Cheung CS, Baron J (2014) Broad shifts in gene expression during early postnatal life are associated with shifts in histone methylation patterns. PLoS One 9(1):e86957CrossRefPubMedPubMedCentralGoogle Scholar
  47. Magklara A, Yen A, Colquitt BM et al (2011) An epigenetic signature for monoallelic olfactory receptor expression. Cell 145:555–570CrossRefPubMedPubMedCentralGoogle Scholar
  48. Marango J, Shimoyama M, Nishio H et al (2008) The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. Blood 111:3145–3154CrossRefPubMedPubMedCentralGoogle Scholar
  49. McCulley DJ, Black BL (2012) Transcription factor pathways and congenital heart disease. Curr Top Dev Biol 100:253–277CrossRefPubMedPubMedCentralGoogle Scholar
  50. Metzger E, Wissmann M, Yin N et al (2005) LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437:436–439PubMedGoogle Scholar
  51. Mummaneni P, Shord SS (2014) Epigenetics and oncology. Pharmacotherapy. doi: 10.1002/phar.1408
  52. Nestorov P, Tardat M, Peters AH (2013) H3K9/HP1 and polycomb: two key epigenetic silencing pathways for gene regulation and embryo development. Curr Top Dev Biol 104:243–291CrossRefPubMedGoogle Scholar
  53. Ng SB, Bigham AW, Buckingham KJ et al (2010) Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet 42(9):790–793CrossRefPubMedPubMedCentralGoogle Scholar
  54. Nguyen AT, Zhang Y (2011) The diverse functions of Dot1 and H3K79 methylation. Genes Dev 25(13):1345–1358CrossRefPubMedPubMedCentralGoogle Scholar
  55. Nguyen AT, Xiao B, Neppl RL et al (2011) DOT1L regulates dystrophin expression and is critical for cardiac function. Genes Dev 25(3):263–274CrossRefPubMedPubMedCentralGoogle Scholar
  56. Nimura K, Ura K, Shiratori H et al (2009) A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome. Nature 460(7252):287–291CrossRefPubMedGoogle Scholar
  57. Olson EN (2006) Gene regulatory networks in the evolution and development of the heart. Science 313(5795):1922–1927CrossRefPubMedPubMedCentralGoogle Scholar
  58. Papangeli I, Scambler P (2013) The 22q11 deletion: DiGeorge and velocardiofacial syndromes and the role of TBX1. Wiley Interdiscip Rev Dev Biol 2(3):393–403CrossRefPubMedGoogle Scholar
  59. Park CY, Pierce SA, von Drehle M et al (2010) skNAC, a Smyd1-interacting transcription factor, is involved in cardiac development and skeletal muscle growth and regeneration. Proc Natl Acad Sci U S A 107(48):20750–20755CrossRefPubMedPubMedCentralGoogle Scholar
  60. Patel SR, Kim D, Levitan I, Dressler GR (2007) The BRCT-domain containing protein PTIP links PAX2 to a histone H3, lysine 4 methyltransferase complex. Dev Cell 13(4):580–592CrossRefPubMedPubMedCentralGoogle Scholar
  61. Pojoga LH, Williams JS, Yao TM et al (2011) Histone demethylase LSD1 deficiency during high-salt diet is associated with enhanced vascular contraction, altered NO-cGMP relaxation pathway, and hypertension. Am J Physiol Heart Circ Physiol 301(5):H1862–H1871CrossRefPubMedPubMedCentralGoogle Scholar
  62. Pokholok DK, Harbison CT, Levine S et al (2005) Genome-wide map of nucleosome acetylation and methylation in yeast. Cell 122(4):517–527CrossRefPubMedGoogle Scholar
  63. Raj A, Rifkin SA, Andersen E, van Oudenaarden A (2010) Variability in gene expression underlies incomplete penetrance. Nature 463:913–918CrossRefPubMedPubMedCentralGoogle Scholar
  64. Randall V, McCue K, Roberts C et al (2009) Great vessel development requires biallelic expression of Chd7 and Tbx1 in pharyngeal ectoderm in mice. J Clin Invest 119(11):3301–3310PubMedPubMedCentralGoogle Scholar
  65. Rasmussen TL, Ma Y, Park CY et al (2015) Smyd1 facilitates heart development by antagonizing oxidative and ER stress responses. PLoS One 10(3):e0121765CrossRefPubMedPubMedCentralGoogle Scholar
  66. Rea S, Eisenhaber F, O’Carroll D et al (2000) Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406(6796):593–599CrossRefPubMedGoogle Scholar
  67. Reddy MA, Villeneuve LM, Wang M et al (2008) Role of the lysine-specific demethylase 1 in the proinflammatory phenotype of vascular smooth muscle cells of diabetic mice. Circ Res 103(6):615–623CrossRefPubMedPubMedCentralGoogle Scholar
  68. Rozek LS, Dolinoy DC, Sartor MA, Omenn GS (2014) Epigenetics: relevance and implications for public health. Annu Rev Public Health 35:105–122CrossRefPubMedPubMedCentralGoogle Scholar
  69. Ruthenburg AJ, Allis CD, Wysocka J (2007) Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Mol Cell 25(1):15–30CrossRefPubMedGoogle Scholar
  70. Sheikh F, Raskin A, Chu PH et al (2008) An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice. J Clin Invest 118(12):3870–3880CrossRefPubMedPubMedCentralGoogle Scholar
  71. Shi YG, Tsukada Y (2013) The discovery of histone demethylases. Cold Spring Harb Perspect Biol 5:a017947CrossRefPubMedPubMedCentralGoogle Scholar
  72. Shi Y, Lan F, Matson C et al (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119:941–953CrossRefPubMedGoogle Scholar
  73. Shilatifard A (2012) The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis. Annu Rev Biochem 81:65–95CrossRefPubMedPubMedCentralGoogle Scholar
  74. Song HK, Hong SE, Kim T et al (2012) Deep RNA sequencing reveals novel cardiac transcriptomic signatures for physiological and pathological hypertrophy. PLoS One 7(4):e35552CrossRefPubMedPubMedCentralGoogle Scholar
  75. Stein AB, Jones TA, Herron TJ et al (2011) Loss of H3K4 methylation destabilizes gene expression patterns and physiological functions in adult murine cardiomyocytes. J Clin Invest 121(7):2641–2650CrossRefPubMedPubMedCentralGoogle Scholar
  76. Stock JK, Giadrossi S, Casanova M et al (2007) Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells. Nat Cell Biol 9(12):1428–1435CrossRefPubMedGoogle Scholar
  77. Strahl B, Allis C (2000) The language of covalent histone modifications. Nature 403(6765):41–45CrossRefPubMedGoogle Scholar
  78. Strobl-Mazzulla PH, Sauka-Spengler T, Bronner-Fraser M (2010) Histone demethylase JmjD2A regulates neural crest specification. Dev Cell 19(3):460–468CrossRefPubMedPubMedCentralGoogle Scholar
  79. Tingare A, Thienpont B, Roderick HL (2013) Epigenetics in the heart: the role of histone modifications in cardiac remodeling. Biochem Soc Trans 41(3):789–796CrossRefPubMedGoogle Scholar
  80. Tobi EW, Goeman JJ, Monajemi R et al (2014) DNA methylation signatures link prenatal famine exposure to growth and metabolism. Nat Commun 5:5592. doi: 10.1038/ncomms6592 CrossRefPubMedPubMedCentralGoogle Scholar
  81. Vermeulen M, Mulder KW, Denissov S et al (2007) Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. Cell 131(1):58–69CrossRefPubMedGoogle Scholar
  82. Vincent SD, Buckingham ME (2010) How to make a heart: the origin and regulation of cardiac progenitor cells. Curr Top Dev Biol 90:1–41CrossRefPubMedGoogle Scholar
  83. Voelkel T, Andresen C, Unger A et al (2013) Lysine methyltransferase Smyd2 regulates Hsp90-mediated protection of the sarcomeric titin springs and cardiac function. Biochim Biophys Acta 1833(4):812–822CrossRefPubMedGoogle Scholar
  84. Voigt P, Tee WW, Reinberg D (2013) A double take on bivalent promoters. Genes Dev 27(12):1318–1338CrossRefPubMedPubMedCentralGoogle Scholar
  85. Wagner EJ, Carpenter PB (2012) Understanding the language of Lys36 methylation at histone H3. Nat Rev Mol Cell Biol 13(2):115–126CrossRefPubMedPubMedCentralGoogle Scholar
  86. Wamstad JA, Alexander JM, Truty RM et al (2012) Dynamic and coordinated epigenetic regulation of developmental transitions in the cardiac lineage. Cell 151(1):206–220CrossRefPubMedPubMedCentralGoogle Scholar
  87. Wolff GL, Kodell RL, Moore SR, Cooney CA (1998) Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J 12(11):949–957PubMedGoogle Scholar
  88. Yang M, Gocke CB, Luo X et al (2006) Structural basis for CoREST-dependent demethylation of nucleosomes by the human LSD1 histone demethylase. Mol Cell 23:377–387CrossRefPubMedGoogle Scholar
  89. Young LC, Hendzel MJ (2013) The oncogenic potential of Jumonji D2 (JMJD2/KDM4) histone demethylase overexpression. Biochem Cell Biol 91(6):369–377CrossRefPubMedGoogle Scholar
  90. Yuan S, Zaidi S, Brueckner M (2013) Congenital heart disease: emerging themes linking genetics and development. Curr Opin Genet Dev 23(3):352–359CrossRefPubMedPubMedCentralGoogle Scholar
  91. Zaidi S, Choi M, Wakimoto H et al (2013) De novo mutations in histone-modifying genes in congenital heart disease. Nature 498(7453):220–223CrossRefPubMedPubMedCentralGoogle Scholar
  92. Zhang QJ, Chen HZ, Wang L et al (2011) The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice. J Clin Invest 121:2447–2456CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Departments of Internal Medical-Cardiology Division and Molecular BiologyUT Southwestern Medical CenterDallasUSA

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