Advertisement

An Introduction to Epigenetics in Cardiovascular Development, Disease, and Sexualization

  • Christine M. Cunningham
  • Mansoureh Eghbali
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1065)

Abstract

Epigenetic regulation of gene expression is integral to cell differentiation, development, and disease. Modes of epigenetic regulation—including DNA methylation, histone modifications, and ncRNA-based regulation—alter chromatin structure, promotor accessibility, and contribute to posttranscriptional modifications. In the cardiovascular system, epigenetic regulation is necessary for proper cardiovascular development and homeostasis, while epigenetic dysfunction is associated with improper cardiac development and disease.

Early sexualization of tissues, including X-inactivation in females and maternal and paternal imprinting, is also orchestrated through epigenetic mechanisms. Furthermore, sex chromosomes encode various sex-specific genes involved in epigenetic regulation, while sex hormones can act as regulatory cofactors that may predispose or protect males and females against developing diseases with a marked sex bias.

The following book chapter summarizes the field of epigenetics in the context of cardiovascular development and disease while also highlighting the role of epigenetic regulation as a powerful source of sex differences within the cardiovascular system.

Keywords

Epigenetics Cardiovascular disease Cardiovascular development Sex differences Sexualization Sex chromosomes Sex hormones 

References

  1. 1.
    Abi Khalil C. The emerging role of epigenetics in cardiovascular disease. Ther Adv Chronic Dis. 2014;5(4):178–87. https://doi.org/10.1177/2040622314529325.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Allis CD, Jenuwein T. The molecular hallmarks of epigenetic control. Nat Rev Genet. 2016;17(8):487–500. https://doi.org/10.1038/nrg.2016.59.CrossRefPubMedGoogle Scholar
  3. 3.
    Arnold AP, Reue K, Eghbali M, Vilain E, Chen X, Ghahramani N, et al. The importance of having two X chromosomes. Philos Trans R Soc Lond Ser B Biol Sci. 2016;371(1688):20150113. https://doi.org/10.1098/rstb.2015.0113.CrossRefGoogle Scholar
  4. 4.
    Balaton BP, Brown CJ. Escape artists of the X chromosome. Trends Genet. 2016;32(6):348–59. https://doi.org/10.1016/j.tig.2016.03.007.CrossRefPubMedGoogle Scholar
  5. 5.
    Balaton BP, Cotton AM, Brown CJ. Derivation of consensus inactivation status for X-linked genes from genome-wide studies. Biol Sex Differ. 2015;6:35. https://doi.org/10.1186/s13293-015-0053-7.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Banka S, Lederer D, Benoit V, Jenkins E, Howard E, Bunstone S, et al. Novel KDM6A (UTX) mutations and a clinical and molecular review of the X-linked kabuki syndrome (KS2). Clin Genet. 2015;87(3):252–8. https://doi.org/10.1111/cge.12363.CrossRefPubMedGoogle Scholar
  7. 7.
    Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21(3):381–95. https://doi.org/10.1038/cr.2011.22.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev. 2009;23(7):781–3. https://doi.org/10.1101/gad.1787609.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bhat-Nakshatri P, Wang G, Collins NR, Thomson MJ, Geistlinger TR, Carroll JS, et al. Estradiol-regulated microRNAs control estradiol response in breast cancer cells. Nucleic Acids Res. 2009;37(14):4850–61. https://doi.org/10.1093/nar/gkp500.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Bloomer LDS, Nelson CP, Eales J, Denniff M, Christofidou P, Debiec R, et al. Male-specific region of the Y chromosome and cardiovascular risk: phylogenetic analysis and gene expression studies. Arterioscler Thromb Vasc Biol. 2013;33(7):1722–7. https://doi.org/10.1161/ATVBAHA.113.301608.CrossRefPubMedGoogle Scholar
  11. 11.
    Brown CJ, Ballabio A, Rupert JL, Lafreniere RG, Grompe M, Tonlorenzi R, Willard HF. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature. 1991;349(6304):38–44. https://doi.org/10.1038/349038a0.CrossRefPubMedGoogle Scholar
  12. 12.
    Brown CJ, Willard HF. The human X-inactivation centre is not required for maintenance of X-chromosome inactivation. Nature. 1994;368(6467):154–6. https://doi.org/10.1038/368154a0.CrossRefPubMedGoogle Scholar
  13. 13.
    Burgoyne PS, Arnold AP. A primer on the use of mouse models for identifying direct sex chromosome effects that cause sex differences in non-gonadal tissues. Biol Sex Differ. 2016;7:68. https://doi.org/10.1186/s13293-016-0115-5.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Cao DJ, Wang ZV, Battiprolu PK, Jiang N, Morales CR, Kong Y, et al. Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by suppressing autophagy. Proc Natl Acad Sci. 2011;108(10):4123–8. https://doi.org/10.1073/pnas.1015081108.CrossRefPubMedGoogle Scholar
  15. 15.
    Carè A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P, et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med. 2007;13(5):613–8. https://doi.org/10.1038/nm1582.CrossRefPubMedGoogle Scholar
  16. 16.
    Castellano L, Giamas G, Jacob J, Coombes RC, Lucchesi W, Thiruchelvam P, et al. The estrogen receptor-α-induced microRNA signature regulates itself and its transcriptional response. Proc Natl Acad Sci. 2009;106(37):15732–7. https://doi.org/10.1073/pnas.0906947106.CrossRefPubMedGoogle Scholar
  17. 17.
    Cedar H, Bergman Y. Programming of DNA methylation patterns. Annu Rev Biochem. 2012;81:97–117. https://doi.org/10.1146/annurev-biochem-052610-091920.CrossRefPubMedGoogle Scholar
  18. 18.
    Chamberlain AA, Lin M, Lister RL, Maslov AA, Wang Y, Suzuki M, et al. DNA methylation is developmentally regulated for genes essential for cardiogenesis. J Am Heart Assoc. 2014;3(3):e000976. https://doi.org/10.1161/JAHA.114.000976.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Chang S, McKinsey TA, Zhang CL, Richardson JA, Hill JA, Olson EN. Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development. Mol Cell Biol. 2004;24(19):8467–76. https://doi.org/10.1128/MCB.24.19.8467-8476.2004.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Charchar FJ, Bloomer LD, Barnes TA, Cowley MJ, Nelson CP, Wang Y, et al. Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome. Lancet. 2012;379(9819):915–22. https://doi.org/10.1016/S0140-6736(11)61453-0.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Charchar FJ, Tomaszewski M, Padmanabhan S, Lacka B, Upton MN, Inglis GC, et al. The Y chromosome effect on blood pressure in two European populations. Hypertension (Dallas, Tex.: 1979). 2002;39(2 Pt 2):353–6.CrossRefGoogle Scholar
  22. 22.
    Chen X, McClusky R, Chen J, Beaven SW, Tontonoz P, Arnold AP, Reue K. The number of x chromosomes causes sex differences in adiposity in mice. PLoS Genet. 2012;8(5):e1002709. https://doi.org/10.1371/journal.pgen.1002709.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Cifuentes-Rojas C, Hernandez AJ, Sarma K, Lee JT. Regulatory interactions between RNA and polycomb repressive complex 2. Mol Cell. 2014;55(2):171–85. https://doi.org/10.1016/j.molcel.2014.05.009.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Clemson CM, McNeil JA, Willard HF, Lawrence JB. XIST RNA paints the inactive X chromosome at interphase: evidence for a novel RNA involved in nuclear/chromosome structure. J Cell Biol. 1996;132(3):259–75. https://doi.org/10.1083/jcb.132.3.259.CrossRefPubMedGoogle Scholar
  25. 25.
    Cortez D, Marin R, Toledo-Flores D, Froidevaux L, Liechti A, Waters PD, et al. Origins and functional evolution of Y chromosomes across mammals. Nature. 2014;508(7497):488–93. https://doi.org/10.1038/nature13151.CrossRefPubMedGoogle Scholar
  26. 26.
    da Rocha ST, Boeva V, Escamilla-Del-Arenal M, Ancelin K, Granier C, Matias NR, et al. Jarid2 is implicated in the initial Xist-induced targeting of PRC2 to the inactive X chromosome. Mol Cell. 2014;53(2):301–16. https://doi.org/10.1016/j.molcel.2014.01.002.CrossRefPubMedGoogle Scholar
  27. 27.
    Dan J, Chen T. Genetic studies on mammalian DNA methyltransferases. In: DNA methyltransferases – role and function. Cham: Springer; 2016. p. 123–50. https://doi.org/10.1007/978-3-319-43624-1_6.CrossRefGoogle Scholar
  28. 28.
    Dong C, Yoon W, Goldschmidt-Clermont PJ. DNA methylation and atherosclerosis. J Nutr. 2002;132(8 Suppl):2406S–9S.CrossRefPubMedGoogle Scholar
  29. 29.
    Du S, Itoh N, Askarinam S, Hill H, Arnold AP, Voskuhl RR. XY sex chromosome complement, compared with XX, in the CNS confers greater neurodegeneration during experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2014;111(7):2806–11. https://doi.org/10.1073/pnas.1307091111.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983;301(5895):89–92. https://doi.org/10.1038/301089a0.CrossRefPubMedGoogle Scholar
  31. 31.
    Fletcher CE, Dart DA, Bevan CL. Interplay between steroid signalling and microRNAs: implications for hormone-dependent cancers. Endocr Relat Cancer. 2014;21(5):R409–29. https://doi.org/10.1530/ERC-14-0208.CrossRefPubMedGoogle Scholar
  32. 32.
    Gillette TG, Hill JA. Readers, writers and erasers: chromatin as the whiteboard of heart disease. Circ Res. 2015;116(7):1245–53. https://doi.org/10.1161/CIRCRESAHA.116.303630.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell. 2007;128(4):635–8. https://doi.org/10.1016/j.cell.2007.02.006.CrossRefPubMedGoogle Scholar
  34. 34.
    Granger A, Abdullah I, Huebner F, Stout A, Wang T, Huebner T, et al. Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice. FASEB J. 2008;22(10):3549–60. https://doi.org/10.1096/fj.08-108548.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Grote P, Wittler L, Hendrix D, Koch F, Währisch S, Beisaw A, et al. The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse. Dev Cell. 2013;24(2):206–14. https://doi.org/10.1016/j.devcel.2012.12.012.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Grunert M, Dorn C, Cui H, Dunkel I, Schulz K, Schoenhals S, et al. Comparative DNA methylation and gene expression analysis identifies novel genes for structural congenital heart diseases. Cardiovasc Res. 2016;112(1):464–77. https://doi.org/10.1093/cvr/cvw195.CrossRefPubMedGoogle Scholar
  37. 37.
    Guo X, Su B, Zhou Z, Sha J. Rapid evolution of mammalian X-linked testis microRNAs. BMC Genomics. 2009;10:97. https://doi.org/10.1186/1471-2164-10-97.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Gusterson RJ, Jazrawi E, Adcock IM, Latchman DS. The transcriptional co-activators CREB-binding protein (CBP) and p300 play a critical role in cardiac hypertrophy that is dependent on their histone acetyltransferase activity. J Biol Chem. 2003;278(9):6838–47. https://doi.org/10.1074/jbc.M211762200.CrossRefPubMedGoogle Scholar
  39. 39.
    Haas J, Frese KS, Park YJ, Keller A, Vogel B, Lindroth AM, et al. Alterations in cardiac DNA methylation in human dilated cardiomyopathy. EMBO Mol Med. 2013;5(3):413–29. https://doi.org/10.1002/emmm.201201553.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Haemmig S, Simion V, Yang D, Deng Y, Feinberg MW. Long noncoding Rnas in cardiovascular disease, diagnosis, and therapy. Curr Opin Cardiol. 2017;32:776. https://doi.org/10.1097/HCO.0000000000000454.CrossRefPubMedGoogle Scholar
  41. 41.
    Han P, Li W, Lin C-H, Yang J, Shang C, Nurnberg ST, et al. A long noncoding RNA protects the heart from pathological hypertrophy. Nature. 2014;514(7520):102–6. https://doi.org/10.1038/nature13596.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Hang CT, Yang J, Han P, Cheng H-L, Shang C, Ashley E, et al. Chromatin regulation by Brg1 underlies heart muscle development and disease. Nature. 2010;466(7302):62–7. https://doi.org/10.1038/nature09130.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Hiura Y, Fukushima Y, Kokubo Y, Okamura T, Goto Y, Nonogi H, et al. Effects of the Y chromosome on cardiovascular risk factors in Japanese men. Hypertens Res. 2008;31(9):1687–94. https://doi.org/10.1291/hypres.31.1687.CrossRefPubMedGoogle Scholar
  44. 44.
    Hughes JF, Skaletsky H, Brown LG, Pyntikova T, Graves T, Fulton RS, et al. Strict evolutionary conservation followed rapid gene loss on human and rhesus Y chromosomes. Nature. 2012;483(7387):82–6. https://doi.org/10.1038/nature10843.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Ikeda S, Kong SW, Lu J, Bisping E, Zhang H, Allen PD, et al. Altered microRNA expression in human heart disease. Physiol Genomics. 2007;31(3):367–73. https://doi.org/10.1152/physiolgenomics.00144.2007.CrossRefPubMedGoogle Scholar
  46. 46.
    Jadhav RR, Ye Z, Huang R-L, Liu J, Hsu P-Y, Huang Y-W, et al. Genome-wide DNA methylation analysis reveals estrogen-mediated epigenetic repression of metallothionein-1 gene cluster in breast cancer. Clin Epigenetics. 2015;7:13. https://doi.org/10.1186/s13148-015-0045-9.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Kaneda R, Takada S, Yamashita Y, Choi YL, Nonaka-Sarukawa M, Soda M, et al. Genome-wide histone methylation profile for heart failure. Genes Cells. 2009;14(1):69–77. https://doi.org/10.1111/j.1365-2443.2008.01252.x.CrossRefPubMedGoogle Scholar
  48. 48.
    Khoury S, Yarows SA, O’Brien TK, Sowers JR. Ambulatory blood pressure monitoring in a nonacademic setting. Effects of age and sex. Am J Hypertens. 1992;5(9):616–23.CrossRefPubMedGoogle Scholar
  49. 49.
    Klattenhoff CA, Scheuermann JC, Surface LE, Bradley RK, Fields PA, Steinhauser ML, et al. Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell. 2013;152(3):570–83. https://doi.org/10.1016/j.cell.2013.01.003.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Latronico MVG, Condorelli G. MicroRNAs and cardiac pathology. Nat Rev Cardiol. 2009;6(6):419–29. https://doi.org/10.1038/nrcardio.2009.56.CrossRefPubMedGoogle Scholar
  51. 51.
    Leader JE, Wang C, Fu M, Pestell RG. Epigenetic regulation of nuclear steroid receptors. Biochem Pharmacol. 2006;72(11):1589–96. https://doi.org/10.1016/j.bcp.2006.05.024.CrossRefPubMedGoogle Scholar
  52. 52.
    Lee JT, Strauss WM, Dausman JA, Jaenisch R. A 450 kb transgene displays properties of the mammalian X-inactivation center. Cell. 1996;86(1):83–94.CrossRefPubMedGoogle Scholar
  53. 53.
    Li J, Chen X, McClusky R, Ruiz-Sundstrom M, Itoh Y, Umar S, et al. The number of X chromosomes influences protection from cardiac ischaemia/reperfusion injury in mice: one X is better than two. Cardiovasc Res. 2014;102(3):375–84. https://doi.org/10.1093/cvr/cvu064.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    McCarthy MI, Hirschhorn JN. Genome-wide association studies: potential next steps on a genetic journey. Hum Mol Genet. 2008;17(R2):R156–65. https://doi.org/10.1093/hmg/ddn289.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    McCarthy MM, Auger AP, Bale TL, De Vries GJ, Dunn GA, Forger NG, et al. The epigenetics of sex differences in the brain. J Neurosci. 2009;29(41):12815–23. https://doi.org/10.1523/JNEUROSCI.3331-09.2009.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Menazza S, Murphy E. The expanding complexity of estrogen receptor signaling in the cardiovascular system. Circ Res. 2016;118(6):994–1007. https://doi.org/10.1161/CIRCRESAHA.115.305376.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol. 2013;13(10):709–21. https://doi.org/10.1038/nri3520.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Morgan CP, Bale TL. Sex differences in microRNA regulation of gene expression: no smoke, just miRs. Biol Sex Differ. 2012;3(1):22. https://doi.org/10.1186/2042-6410-3-22.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Movassagh M, Choy M-K, Knowles DA, Cordeddu L, Haider S, Down T, et al. Distinct epigenomic features in end-stage failing human hearts. Circulation. 2011;124(22):2411–22. https://doi.org/10.1161/CIRCULATIONAHA.111.040071.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Nikitina T, Shi X, Ghosh RP, Horowitz-Scherer RA, Hansen JC, Woodcock CL. Multiple modes of interaction between the methylated DNA binding protein MeCP2 and chromatin. Mol Cell Biol. 2007;27(3):864–77. https://doi.org/10.1128/MCB.01593-06.CrossRefPubMedGoogle Scholar
  61. 61.
    Norris DP, Patel D, Kay GF, Penny GD, Brockdorff N, Sheardown SA, Rastan S. Evidence that random and imprinted Xist expression is controlled by preemptive methylation. Cell. 1994;77(1):41–51.CrossRefPubMedGoogle Scholar
  62. 62.
    Ooi JYY, Tuano NK, Rafehi H, Gao X-M, Ziemann M, Du X-J, El-Osta A. HDAC inhibition attenuates cardiac hypertrophy by acetylation and deacetylation of target genes. Epigenetics. 2015;10(5):418–30. https://doi.org/10.1080/15592294.2015.1024406.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Papageorgiou N, Tousoulis D, Androulakis E, Siasos G, Briasoulis A, Vogiatzi G, et al. The role of microRNAs in cardiovascular disease. Curr Med Chem. 2012;19(16):2605–10.CrossRefPubMedGoogle Scholar
  64. 64.
    Papait R, Cattaneo P, Kunderfranco P, Greco C, Carullo P, Guffanti A, et al. Genome-wide analysis of histone marks identifying an epigenetic signature of promoters and enhancers underlying cardiac hypertrophy. Proc Natl Acad Sci U S A. 2013;110(50):20164–9. https://doi.org/10.1073/pnas.1315155110.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Papait R, Serio S, Pagiatakis C, Rusconi F, Carullo P, Mazzola M, et al. Histone methyltransferase G9a is required for cardiomyocyte homeostasis and hypertrophy. Circulation. 2017;136(13):1233–46. https://doi.org/10.1161/CIRCULATIONAHA.117.028561.CrossRefPubMedGoogle Scholar
  66. 66.
    Pasquinelli AE. MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet. 2012;13(4):271–82. https://doi.org/10.1038/nrg3162.CrossRefPubMedGoogle Scholar
  67. 67.
    Queirós AM, Eschen C, Fliegner D, Kararigas G, Dworatzek E, Westphal C, et al. Sex- and estrogen-dependent regulation of a miRNA network in the healthy and hypertrophied heart. Int J Cardiol. 2013;169(5):331–8. https://doi.org/10.1016/j.ijcard.2013.09.002.CrossRefPubMedGoogle Scholar
  68. 68.
    Rafehi H, Balcerczyk A, Lunke S, Kaspi A, Ziemann M, Kn H, et al. Vascular histone deacetylation by pharmacological HDAC inhibition. Genome Res. 2014;24(8):1271–84. https://doi.org/10.1101/gr.168781.113.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Rosa-Garrido M, Chapski DJ, Schmitt AD, Kimball TH, Karbassi E, Monte E, et al. High resolution mapping of chromatin conformation in cardiac myocytes reveals structural remodeling of the epigenome in heart failure. Circulation. 2017;136:1613. https://doi.org/10.1161/CIRCULATIONAHA.117.029430.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Rosales W, Carulla J, García J, Vargas D, Lizcano F. Role of histone demethylases in cardiomyocytes induced to hypertrophy. Biomed Res Int. 2016;2016(2634976):1. https://doi.org/10.1155/2016/2634976.CrossRefGoogle Scholar
  71. 71.
    Santos-Rebouças CB, Fintelman-Rodrigues N, Jensen LR, Kuss AW, Ribeiro MG, Campos M, et al. A novel nonsense mutation in KDM5C/JARID1C gene causing intellectual disability, short stature and speech delay. Neurosci Lett. 2011;498(1):67–71. https://doi.org/10.1016/j.neulet.2011.04.065.CrossRefPubMedGoogle Scholar
  72. 72.
    Sharma S, Eghbali M. Influence of sex differences on microRNA gene regulation in disease. Biol Sex Differ. 2014;5(1):3. https://doi.org/10.1186/2042-6410-5-3.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Shin S, Janknecht R. Activation of androgen receptor by histone demethylases JMJD2A and JMJD2D. Biochem Biophys Res Commun. 2007;359(3):742–6. https://doi.org/10.1016/j.bbrc.2007.05.179.CrossRefPubMedGoogle Scholar
  74. 74.
    Shpargel KB, Sengoku T, Yokoyama S, Magnuson T. UTX and UTY demonstrate histone demethylase-independent function in mouse embryonic development. PLoS Genet. 2012;8(9):e1002964. https://doi.org/10.1371/journal.pgen.1002964.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Snijders Blok L, Madsen E, Juusola J, Gilissen C, Baralle D, Reijnders MRF, et al. Mutations in DDX3X are a common cause of unexplained intellectual disability with gender-specific effects on Wnt signaling. Am J Hum Genet. 2015;97(2):343–52. https://doi.org/10.1016/j.ajhg.2015.07.004.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000;403(6765):41–5. https://doi.org/10.1038/47412.CrossRefPubMedGoogle Scholar
  77. 77.
    Suzuki MM, Bird A. DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet. 2008;9(6):465–76. https://doi.org/10.1038/nrg2341.CrossRefPubMedGoogle Scholar
  78. 78.
    Trivedi CM, Luo Y, Yin Z, Zhang M, Zhu W, Wang T, et al. Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity. Nat Med. 2007;13(3):324–31. https://doi.org/10.1038/nm1552.CrossRefPubMedGoogle Scholar
  79. 79.
    Umar S, Cunningham CM, Itoh Y, Moazeni S, Vaillancourt M, Sarji S, et al. The Y chromosome plays a protective role in experimental hypoxic pulmonary hypertension. Am J Respir Crit Care Med. 2017. https://doi.org/10.1164/rccm.201707-1345LE.
  80. 80.
    Umer M, Herceg Z. Deciphering the epigenetic code: an overview of DNA methylation analysis methods. Antioxid Redox Signal. 2013;18(15):1972–86. https://doi.org/10.1089/ars.2012.4923.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Valencia-Morales M d P, Zaina S, Heyn H, Carmona FJ, Varol N, Sayols S, et al. The DNA methylation drift of the atherosclerotic aorta increases with lesion progression. BMC Med Genet. 2015;8:7. https://doi.org/10.1186/s12920-015-0085-1.CrossRefGoogle Scholar
  82. 82.
    Waddington CH. The epigenotype. Endeavour. 1942;1:18–20.Google Scholar
  83. 83.
    Waddington CH. The strategy of the genes, Routledge library editions: 20th century science. London: Routledge; 2014.CrossRefGoogle Scholar
  84. 84.
    Wang H, Maurano MT, Qu H, Varley KE, Gertz J, Pauli F, et al. Widespread plasticity in CTCF occupancy linked to DNA methylation. Genome Res. 2012;22(9):1680–8. https://doi.org/10.1101/gr.136101.111.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Wang K, Liu F, Zhou L-Y, Long B, Yuan S-M, Wang Y, et al. The long noncoding RNA CHRF regulates cardiac hypertrophy by targeting miR-489. Circ Res. 2014a;114(9):1377–88. https://doi.org/10.1161/CIRCRESAHA.114.302476.CrossRefPubMedGoogle Scholar
  86. 86.
    Wang K, Long B, Zhou L-Y, Liu F, Zhou Q-Y, Liu C-Y, et al. CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation. Nat Commun. 2014b;5:3596. https://doi.org/10.1038/ncomms4596.CrossRefPubMedGoogle Scholar
  87. 87.
    Wang Z, Zhang X-J, Ji Y-X, Zhang P, Deng K-Q, Gong J, et al. The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy. Nat Med. 2016;22(10):1131–9. https://doi.org/10.1038/nm.4179.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Wu X, Zhang Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet. 2017;18(9):517–34. https://doi.org/10.1038/nrg.2017.33.CrossRefPubMedGoogle Scholar
  89. 89.
    Xiao ZG, Shen J, Zhang L, Li LF, Li MX, Hu W, et al. The roles of histone demethylase UTX and JMJD3 (KDM6B) in cancers: current progress and future perspectives. Curr Med Chem. 2016;23:3687–96.CrossRefPubMedGoogle Scholar
  90. 90.
    Yamauchi Y, Riel JM, Stoytcheva Z, Ward MA. Two Y genes can replace the entire Y chromosome for assisted reproduction in the mouse. Science. 2014;343(6166):69–72. https://doi.org/10.1126/science.1242544.CrossRefPubMedGoogle Scholar
  91. 91.
    Ying AK, Hassanain HH, Roos CM, Smiraglia DJ, Issa JJ, Michler RE, et al. Methylation of the estrogen receptor-alpha gene promoter is selectively increased in proliferating human aortic smooth muscle cells. Cardiovasc Res. 2000;46(1):172–9.CrossRefPubMedGoogle Scholar
  92. 92.
    Yoon S, Eom GH. HDAC and HDAC inhibitor: from Cancer to cardiovascular diseases. Chonnam Med J. 2016;52(1):1–11. https://doi.org/10.4068/cmj.2016.52.1.1.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Zhang CL, McKinsey TA, Chang S, Antos CL, Hill JA, Olson EN. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell. 2002;110(4):479–88.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Zhang Q-J, Chen H-Z, Wang L, Liu D-P, Hill JA, Liu Z-P. The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice. J Clin Invest. 2011;121(6):2447–56. https://doi.org/10.1172/JCI46277.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Zhang X, Ho S-M. Epigenetics meets endocrinology. J Mol Endocrinol. 2011;46(1):R11–32. https://doi.org/10.1677/JME-10-0053.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Zhao J, Sun BK, Erwin JA, Song J-J, Lee JT. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science (New York, N.Y.). 2008;322(5902):750–6. https://doi.org/10.1126/science.1163045.CrossRefGoogle Scholar
  97. 97.
    Zhong J, Agha G, Baccarelli AA. The role of DNA methylation in cardiovascular risk and disease: methodological aspects, study design, and data analysis for epidemiological studies. Circ Res. 2016;118(1):119–31. https://doi.org/10.1161/CIRCRESAHA.115.305206.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Anesthesiology and Perioperative Medicine, Division of Molecular MedicineDavid Geffen School of Medicine at University of California Los AngelesLos AngelesUSA

Personalised recommendations