Research Progress on DNA Methylation in the Pathogenesis of Cardiac Hypertrophy

Kexin YI, Xin LIU, Xiushan WU, Yongqing LI

Life Sci Res ›› 2025, Vol. 29 ›› Issue (5) : 398-405.

Home Journals Life Science Research
Life Science Research

Abbreviation (ISO4): Life Sci Res      Editor in chief:

About  /  Aim & scope  /  Editorial board  /  Indexed  /  Contact  / 
Life Sci Res ›› 2025, Vol. 29 ›› Issue (5) : 398-405. DOI: 10.16605/j.cnki.1007-7847.2025.02.0121
BASIC MEDICINE

Research Progress on DNA Methylation in the Pathogenesis of Cardiac Hypertrophy

Author information +
History +

Abstract

Cardiac hypertrophy is a process of cardiac adaptive and pathological remodeling, which is usually closely related to increased cardiac workload, chronic stress, and occurrence and development of heart di-sease. In recent years, the role of DNA methylation in cardiac hypertrophy and dysfunction has received ex-tensive attention as an important epigenetic modification mechanism. This article reviews the mechanism of DNA methylation in cardiac hypertrophy and explores its potential effects on cardiac development, gene ex-pression regulation and disease treatment, aiming to provide a new theoretical basis and potential interven-tion targets for the prevention and treatment of cardiac hypertrophy.

Key words

cardiac hypertrophy / DNA methylation / DNA methyltransferase (DNMT) / DNMT inhibitor

Cite this article

Download Citations
Kexin YI , Xin LIU , Xiushan WU , et al. Research Progress on DNA Methylation in the Pathogenesis of Cardiac Hypertrophy[J]. Life Science Research. 2025, 29(5): 398-405 https://doi.org/10.16605/j.cnki.1007-7847.2025.02.0121

References

[1]
World Heart Federation. World Heart Report 2023[EB/OL]. [2024-09-15]. https://heartreport23.world-heart-federation.org/.
[2]
HILL J A, OLSON E N. Cardiac plasticity[J]. New England Jour-nal of Medicine, 2008, 358(13): 1370-1380.
[3]
WEEKS K L, MCMULLEN J R. The athlete’s heart vs. the fai-ling heart: can signaling explain the two distinct outcomes?[J]. Physiology, 2011, 26(2): 97-105.
[4]
THAM Y K, BERNARDO B C, OOI J Y Y, et al. Pathophysio-logy of cardiac hypertrophy and heart failure: signaling path-ways and novel therapeutic targets[J]. Archives of Toxicology, 2015, 89(9): 1401-1438.
[5]
MARIAN A J, BRAUNWALD E. Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy[J]. Circulation Research, 2017, 121(7): 749-770.
[6]
LIU C F, TANG W H W. Epigenetics in cardiac hypertrophy and heart failure[J]. JACC: Basic to Translational Science, 2019, 4(8): 976-993.
[7]
NAKAMURA M, SADOSHIMA J. Mechanisms of physiological and pathological cardiac hypertrophy[J]. Nature Reviews Cardio-logy, 2018, 15(7): 387-407.
[8]
SCHIATTARELLA G G, HILL J A. Inhibition of hypertrophy is a good therapeutic strategy in ventricular pressure overload[J]. Circulation, 2015, 131(16): 1435-1447.
[9]
PORTELA A, ESTELLER M. Epigenetic modifications and hu-man disease[J]. Nature Biotechnology, 2010, 28(10): 1057-1068.
[10]
KISELEV I, KOZIN M, BAULINA N, et al. Novel genes invol-ved in hypertrophic cardiomyopathy: data of transcriptome and methylome profiling[J]. International Journal of Molecular Scien-ces, 2022, 23(23): 15280.
[11]
GREENBERG M V C, BOURC′HIS D. The diverse roles of DNA methylation in mammalian development and disease[J]. Nature Reviews Molecular Cell Biology, 2019, 20(10): 590-607.
[12]
SCHULZ M, TEISSANDIER A, DE LA MATA SANTAELLA E, et al. DNA methylation restricts coordinated germline and neu-ral fates in embryonic stem cell differentiation[J]. Nature Struc-tural & Molecular Biology, 2024, 31(1): 102-114.
[13]
SMITH Z D, MEISSNER A. DNA methylation: roles in mam-malian development[J]. Nature Reviews Genetics, 2013, 14(3): 204-220.
[14]
STEFANSSON O A, SIGURPALSDOTTIR B D, ROGNVALDS-SON S, et al. The correlation between CpG methylation and gene expression is driven by sequence variants[J]. Nature Ge-netics, 2024, 56(8): 1624-1631.
[15]
DU Q, LUU P L, STIRZAKER C, et al. Methyl-CpG-binding domain proteins: readers of the epigenome[J]. Epigenomics, 2015, 7(6): 1051-1073.
[16]
DONG Q, LI X, WANG C Z, et al. Roles of the CSE1L-mediated nuclear import pathway in epigenetic silencing[J]. Proceedings of the National Academy of Sciences of USA, 2018, 115(17): E4013-E4022.
[17]
DOMCKE S, BARDET A F, ADRIAN GINNO P, et al. Com-petition between DNA methylation and transcription factors de-termines binding of NRF1[J]. Nature, 2015, 528(7583): 575-579.
[18]
HARRIS C J, SCHEIBE M, WONGPALEE S P, et al. A DNA methylation reader complex that enhances gene transcription[J]. Science, 2018, 362(6419): 1182-1186.
[19]
CHATTOPADHYAYA S, GHOSAL S. DNA methylation: a saga of genome maintenance in hematological perspective[J]. Human Cell, 2022, 35(2): 448-461.
[20]
LI Y L, CHEN X, LU C. The interplay between DNA and his-tone methylation: molecular mechanisms and disease implica-tions[J]. EMBO Reports, 2021, 22(5): e51803.
[21]
LYKO F. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation[J]. Nature Reviews Genetics, 2018, 19(2): 81-92.
[22]
MOORE L D, LE T, FAN G P. DNA methylation and its basic function[J]. Neuropsychopharmacology, 2013, 38(1): 23-38.
[23]
ZHANG X C, ZHANG Y, WANG C F, et al. TET (ten-eleven translocation) family proteins: structure, biological functions and applications[J]. Signal Transduction and Targeted Therapy, 2023, 8: 297.
[24]
WU X J, ZHANG Y. TET-mediated active DNA demethylation: mechanism, function and beyond[J]. Nature Reviews Genetics, 2017, 18(9): 517-534.
[25]
TAN K, FOO R, LOH M. Cardiomyopathy in Asian cohorts: ge-netic and epigenetic insights[J]. Circulation: Genomic and Pre-cision Medicine, 2023, 16(5): 496-506.
[26]
SABIA C, PICASCIA A, GRIMALDI V, et al. The epigenetic promise to improve prognosis of heart failure and heart trans-plantation[J]. Transplantation Reviews, 2017, 31(4): 249-256.
[27]
STENZIG J, HIRT M N, LÖSER A, et al. DNA methylation in an engineered heart tissue model of cardiac hypertrophy: com-mon signatures and effects of DNA methylation inhibitors[J]. Ba-sic Research in Cardiology, 2016, 111: 9.
[28]
SHI H C, CHEN S, MENG F W, et al. Epigenome-wide DNA methylation profiling in comparison between pathological and physiological hypertrophy of human cardiomyocytes[J]. Frontiers in Genetics, 2023, 14: 1264382.
[29]
GILSBACH R, PREISSL S, GRÜNING B A, et al. Dynamic DNA methylation orchestrates cardiomyocyte development, maturation and disease[J]. Nature Communications, 2014, 5: 5288.
[30]
XIAO D L, DASGUPTA C, CHEN M, et al. Inhibition of DNA methylation reverses norepinephrine-induced cardiac hypertro-phy in rats[J]. Cardiovascular Research, 2014, 101(3): 373-382.
[31]
LIU L Z, HE X, ZHAO M, et al. Regulation of DNA methyla-tion and 2-OG/TET signaling by choline alleviated cardiac hy-pertrophy in spontaneously hypertensive rats[J]. Journal of Mo-lecular and Cellular Cardiology, 2019, 128: 26-37.
[32]
LI X Y, FAN H L, SONG X T, et al. DNA methylome and transcriptome profiling reveal key electrophysiology and im-mune dysregulation in hypertrophic cardiomyopathy[J]. Epige-netics, 2023, 18(1): 2195307.
[33]
HAN P, LI W, YANG J, et al. Epigenetic response to environ-mental stress: assembly of BRG1-G9a/GLP-DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts[J]. Biochimica et Biophysica Acta-Molecular Cell Re-search, 2016, 1863(7 Pt B): 1772-1781.
[34]
NAROLSKA N A, EIRAS S, VAN LOON R B, et al. Myosin hea-vy chain composition and the economy of contraction in healthy and diseased human myocardium[J]. Journal of Muscle Research and Cell Motility, 2005, 26(1): 39-48.
[35]
GAO J P, LIU M Y, LU M J, et al. Integrative analysis of trans-criptome, DNA methylome, and chromatin accessibility reveals candidate therapeutic targets in hypertrophic cardiomyopathy[J]. Protein & Cell, 2024, 15(11): 796-817.
[36]
ANGRISANO T, SCHIATTARELLA G G, KELLER S, et al. Epi-genetic switch at Atp2a2 and Myh7 gene promoters in pres-sure overload-induced heart failure[J]. PLoS One, 2014, 9(9): e106024.
[37]
LIU Z H, NI J Y, LI L, et al. SERCA2a: a key protein in the Ca2+ cycle of the heart failure[J]. Heart Failure Reviews, 2020, 25(3): 523-535.
[38]
CHATURVEDI P, TYAGI S C. Epigenetic silencing of TIMP4 in heart failure[J]. Journal of Cellular and Molecular Medicine, 2016, 20(11): 2089-2101.
[39]
CHENG M D, LI C L, PEI X Y, et al. Integrative analysis of DNA methylome and transcriptome reveals epigenetic regula-tion of bisphenols-induced cardiomyocyte hypertrophy[J]. Eco-toxicology and Environmental Safety, 2023, 263: 115391.
[40]
KIM M Y, PARK E R, CHO E H, et al. Depletion of protea-some subunit PSMD1 induces cancer cell death via protein ubi-quitination and DNA damage, irrespective of p53 status[J]. Scien-tific Reports, 2024, 14: 7997.
[41]
ZHOU X J, WANG G X, TIAN C H, et al. Inhibition of DUSP18 impairs cholesterol biosynthesis and promotes anti-tumor im-munity in colorectal cancer[J]. Nature Communications, 2024, 15: 5851.
[42]
JACOB C, KITAGAWA A, SIGNORETTI C, et al. Mediterra-nean G6PD variant mitigates expression of DNA methyltrans-ferases and right heart pressure in experimental model of pul-monary hypertension[J]. The Journal of Biological Chemistry, 2022, 298(12): 102691.
[43]
WU T T, MA Y W, ZHANG X, et al. Myocardial tissue-spe-cific Dnmt1 knockout in rats protects against pathological in-jury induced by adriamycin[J]. Laboratory Investigation, 2020, 100(7): 974-985.
[44]
WANG Y Y, GAO B, YANG Y, et al. Histone deacetylase 3 suppresses the expression of SHP-1 via deacetylation of DNMT1 to promote heart failure[J]. Life Sciences, 2022, 292: 119552.
[45]
LI Q H, WU J X, XU Y J, et al. Role of RASEF hypermethyla-tion in cigarette smoke-induced pulmonary arterial smooth muscle remodeling[J]. Respiratory Research, 2019, 20: 52.
[46]
ZHANG X D, NIE Y H, ZHANG R, et al. Reduced DNMT1 levels induce cell apoptosis via upregulation of METTL3 in cardiac hypertrophy[J]. Heliyon, 2024, 10(3): e24572.
[47]
SANO S, OSHIMA K, WANG Y, et al. CRISPR-mediated gene editing to assess the roles of Tet2 and Dnmt3a in clonal he-matopoiesis and cardiovascular disease[J]. Circulation Research, 2018, 123(3): 335-341.
[48]
SASAKI K, HARA S, YAMAKAMI R, et al. Ectopic expression of DNA methyltransferases DNMT3A2 and DNMT3L leads to aberrant hypermethylation and postnatal lethality in mice[J]. Mo-lecular Reproduction and Development, 2019, 86(6): 614-623.
[49]
MADSEN A, KRAUSE J, HÖPPNER G, et al. Hypertrophic sig-naling compensates for contractile and metabolic consequences of DNA methyltransferase 3A loss in human cardiomyocytes[J]. Journal of Molecular and Cellular Cardiology, 2021, 154: 115-123.
[50]
VUJIC A, ROBINSON E L, ITO M, et al. Experimental heart failure modelled by the cardiomyocyte-specific loss of an epi-genome modifier, DNMT3B[J]. Journal of Molecular and Cellu-lar Cardiology, 2015, 82: 174-183.
[51]
LÓPEZ V, FERNÁNDEZ A F, FRAGA M F. The role of 5-hy-droxymethylcytosine in development, aging and age-related di-seases[J]. Ageing Research Reviews, 2017, 37: 28-38.
[52]
GRECO C M, KUNDERFRANCO P, RUBINO M, et al. DNA hydroxymethylation controls cardiomyocyte gene expression in development and hypertrophy[J]. Nature Communications, 2016, 7: 12418.
[53]
TAO H K, XU W Z, QU W Z, et al. Loss of ten-eleven trans-location 2 induces cardiac hypertrophy and fibrosis through mo-dulating ERK signaling pathway[J]. Human Molecular Genetics, 2021, 30(10): 865-879.
[54]
CICCARONE F, CASTELLI S, IOANNILLI L, et al. High dietary fat intake affects DNA methylation/hydroxymethylation in mouse heart: epigenetic hints for obesity-related cardiac dysfunction[J]. Molecular Nutrition & Food Research, 2019, 63(4): e1800970.
[55]
HUANG L X, XI Z H, WANG C G, et al. Phenanthrene expo-sure induces cardiac hypertrophy via reducing miR-133a expres-sion by DNA methylation[J]. Scientific Reports, 2016, 6: 20105.
[56]
PORRELLO E R. MicroRNAs in cardiac development and re-generation[J]. Clinical Science, 2013, 125(4): 151-166.
[57]
CHAHROUR M, JUNG S Y, SHAW C, et al. MeCP2, a key con-tributor to neurological disease, activates and represses tran-scription[J]. Science, 2008, 320(5880): 1224-1229.
[58]
MAYER S C, GILSBACH R, PREISSL S, et al. Adrenergic re-pression of the epigenetic reader MeCP2 facilitates cardiac adap-tation in chronic heart failure[J]. Circulation Research, 2015, 117(7): 622-633.
[59]
KUNERT S, LINHARD V, WEIRICH S, et al. The MECP2-TRD domain interacts with the DNMT3A-ADD domain at the H3-tail binding site[J]. Protein Science, 2023, 32(1): e4542.
[60]
BOXER L D, RENTHAL W, GREBEN A W, et al. MeCP2 re-presses the rate of transcriptional initiation of highly methylated long genes[J]. Molecular Cell, 2020, 77(2): 294-309.e9.
[61]
YU J, XIE T L, WANG Z, et al. DNA methyltransferases: emer-ging targets for the discovery of inhibitors as potent anticancer drugs[J]. Drug Discovery Today, 2019, 24(12): 2323-2331.
[62]
HU C H, LIU X H, ZENG Y, et al. DNA methyltransferase in-hibitors combination therapy for the treatment of solid tumor: mechanism and clinical application[J]. Clinical Epigenetics, 2021, 13: 166.
[63]
DERISSEN E J B, BEIJNEN J H, SCHELLENS J H M. Con-cise drug review: azacitidine and decitabine[J]. The Oncologist, 2013, 18(5): 619-624.
[64]
FANG X F, ROBINSON J, WANG-HU J, et al. cAMP induces hypertrophy and alters DNA methylation in HL-1 cardiomyo-cytes[J]. American Journal of Physiology Cell Physiology, 2015, 309(6): C425-C436.
[65]
WATSON C J, HORGAN S, NEARY R, et al. Epigenetic therapy for the treatment of hypertension-induced cardiac hypertrophy and fibrosis[J]. Journal of Cardiovascular Pharmacology and The-rapeutics, 2016, 21(1): 127-137.
[66]
ASGATAY S, CHAMPION C, MARLOIE G, et al. Synthesis and evaluation of analogues of N-phthaloyl-L-tryptophan (RG108) as inhibitors of DNA methyltransferase 1[J]. Journal of Medici-nal Chemistry, 2014, 57(2): 421-434.
[67]
STENZIG J, SCHNEEBERGER Y, LÖSER A, et al. Pharmaco-logical inhibition of DNA methylation attenuates pressure over-load-induced cardiac hypertrophy in rats[J]. Journal of Molecu-lar and Cellular Cardiology, 2018, 120: 53-63.
[68]
UDDIN M G, FANDY T E. DNA methylation inhibitors: retro-spective and perspective view[J]. Advances in Cancer Research, 2021, 152: 205-223.
[69]
TAYLOR A L, ZIESCHE S, YANCY C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart fai-lure[J]. New England Journal of Medicine, 2004, 351(20): 2049-2057.
[70]
KHAZANIE P, LIANG L, CURTIS L H, et al. Clinical effec-tiveness of hydralazine-isosorbide dinitrate therapy in patients with heart failure and reduced ejection fraction: findings from the get with the guidelines-heart failure registry[J]. Circulation: Heart Failure, 2016, 9(2): e002444.

Accesses

Citation

Detail

Sections
Recommended

/

〈 〉