Epigenetics and Mechanobiology in Heart Development and Congenital Heart Disease

Overview

Journal Diseases

Date 2019 Sep 5

PMID 31480510

Citations 27

Authors

Dillon K Jarrell

Mallory L Lennon

Jeffrey G Jacot

Affiliations

Soon will be listed here.

Abstract

Congenital heart disease (CHD) is the most common birth defect worldwide and the number one killer of live-born infants in the United States. Heart development occurs early in embryogenesis and involves complex interactions between multiple cell populations, limiting the understanding and consequent treatment of CHD. Furthermore, genome sequencing has largely failed to predict or yield therapeutics for CHD. In addition to the underlying genome, epigenetics and mechanobiology both drive heart development. A growing body of evidence implicates the aberrant regulation of these two extra-genomic systems in the pathogenesis of CHD. In this review, we describe the stages of human heart development and the heart defects known to manifest at each stage. Next, we discuss the distinct and overlapping roles of epigenetics and mechanobiology in normal development and in the pathogenesis of CHD. Finally, we highlight recent advances in the identification of novel epigenetic biomarkers and environmental risk factors that may be useful for improved diagnosis and further elucidation of CHD etiology.

Citing Articles

Cardiac Markers in Pediatric Laboratory Medicine: Critical Review.

Zrinski Topic R, Lenicek Krleza J Diagnostics (Basel). 2025; 15(2).

PMID: 39857049 PMC: 11763470. DOI: 10.3390/diagnostics15020165.

Missense mutations in the CITED2 gene may contribute to congenital heart disease.

Yaqoob H, Ahmad H, Ali S, Patel N, Arif A BMC Cardiovasc Disord. 2024; 24(1):516.

PMID: 39333893 PMC: 11429617. DOI: 10.1186/s12872-024-04035-2.

Cardiac Development and Factors Influencing the Development of Congenital Heart Defects (CHDs): Part I.

Zubrzycki M, Schramm R, Costard-Jackle A, Grohmann J, Gummert J, Zubrzycka M Int J Mol Sci. 2024; 25(13).

PMID: 39000221 PMC: 11241401. DOI: 10.3390/ijms25137117.

Mechanobiology of Adipocytes.

Blade S, Falkowski D, Bachand S, Pagano S, Chin L Biology (Basel). 2024; 13(6).

PMID: 38927314 PMC: 11200640. DOI: 10.3390/biology13060434.

Mechanically induced alterations in chromatin architecture guide the balance between cell plasticity and mechanical memory.

Scott A, Rafuse M, Neu C Front Cell Dev Biol. 2023; 11:1084759.

PMID: 37143893 PMC: 10151697. DOI: 10.3389/fcell.2023.1084759.

References

Zhou Z, Tang A, Wong W, Bamezai S, Goddard L, Shenkar R . Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature. 2016; 532(7597):122-6. PMC: 4864035. DOI: 10.1038/nature17178. View

Minot C . ON A HITHERTO UNRECOGNIZED FORM OF BLOOD CIRCULATION WITHOUT CAPILLARIES IN THE ORGANS OF VERTEBRATES. J Boston Soc Med Sci. 2009; 4(6):133-134. PMC: 2121886. View

Yuan S, Zaidi S, Brueckner M . Congenital heart disease: emerging themes linking genetics and development. Curr Opin Genet Dev. 2013; 23(3):352-9. PMC: 4154700. DOI: 10.1016/j.gde.2013.05.004. View

Luxan G, DAmato G, MacGrogan D, de la Pompa J . Endocardial Notch Signaling in Cardiac Development and Disease. Circ Res. 2015; 118(1):e1-e18. DOI: 10.1161/CIRCRESAHA.115.305350. View

Kurdyukov S, Bullock M . DNA Methylation Analysis: Choosing the Right Method. Biology (Basel). 2016; 5(1). PMC: 4810160. DOI: 10.3390/biology5010003. View

Boselli F, Steed E, Freund J, Vermot J . Anisotropic shear stress patterns predict the orientation of convergent tissue movements in the embryonic heart. Development. 2017; 144(23):4322-4327. PMC: 5769631. DOI: 10.1242/dev.152124. View

Lee S, Lee J, Lee S . UTX, a histone H3-lysine 27 demethylase, acts as a critical switch to activate the cardiac developmental program. Dev Cell. 2011; 22(1):25-37. PMC: 4111644. DOI: 10.1016/j.devcel.2011.11.009. View

Huang N, Serpooshan V, Morris V, Sayed N, Pardon G, Abilez O . Big bottlenecks in cardiovascular tissue engineering. Commun Biol. 2018; 1:199. PMC: 6249300. DOI: 10.1038/s42003-018-0202-8. View

Esposito G, Butler T, Blue G, Cole A, Sholler G, Kirk E . Somatic mutations in NKX2–5, GATA4, and HAND1 are not a common cause of tetralogy of Fallot or hypoplastic left heart. Am J Med Genet A. 2011; 155A(10):2416-21. DOI: 10.1002/ajmg.a.34187. View

10.

Grunert M, Dorn C, Cui H, Dunkel I, Schulz K, Schoenhals S . Comparative DNA methylation and gene expression analysis identifies novel genes for structural congenital heart diseases. Cardiovasc Res. 2016; 112(1):464-77. DOI: 10.1093/cvr/cvw195. View

11.

Heckel E, Boselli F, Roth S, Krudewig A, Belting H, Charvin G . Oscillatory Flow Modulates Mechanosensitive klf2a Expression through trpv4 and trpp2 during Heart Valve Development. Curr Biol. 2015; 25(10):1354-61. DOI: 10.1016/j.cub.2015.03.038. View

12.

Santini M, Forte E, Harvey R, Kovacic J . Developmental origin and lineage plasticity of endogenous cardiac stem cells. Development. 2016; 143(8):1242-58. PMC: 4852509. DOI: 10.1242/dev.111591. View

13.

Nimura K, Ura K, Shiratori H, Ikawa M, Okabe M, Schwartz R . A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome. Nature. 2009; 460(7252):287-91. DOI: 10.1038/nature08086. View

14.

Cai C, Liang X, Shi Y, Chu P, Pfaff S, Chen J . Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell. 2003; 5(6):877-89. PMC: 5578462. DOI: 10.1016/s1534-5807(03)00363-0. View

15.

Li Y, Klena N, Gabriel G, Liu X, Kim A, Lemke K . Global genetic analysis in mice unveils central role for cilia in congenital heart disease. Nature. 2015; 521(7553):520-4. PMC: 4617540. DOI: 10.1038/nature14269. View

16.

Wang Y, Wu B, Chamberlain A, Lui W, Koirala P, Susztak K . Endocardial to myocardial notch-wnt-bmp axis regulates early heart valve development. PLoS One. 2013; 8(4):e60244. PMC: 3613384. DOI: 10.1371/journal.pone.0060244. View

17.

Liang D, Xu X, Deng F, Feng J, Zhang H, Liu Y . miRNA-940 reduction contributes to human Tetralogy of Fallot development. J Cell Mol Med. 2014; 18(9):1830-9. PMC: 4196658. DOI: 10.1111/jcmm.12309. View

18.

Stainier D, Weinstein B, Detrich 3rd H, Zon L, Fishman M . Cloche, an early acting zebrafish gene, is required by both the endothelial and hematopoietic lineages. Development. 1995; 121(10):3141-50. DOI: 10.1242/dev.121.10.3141. View

19.

Zhao Y, Ransom J, Li A, Vedantham V, von Drehle M, Muth A . Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell. 2007; 129(2):303-17. DOI: 10.1016/j.cell.2007.03.030. View

20.

Buckingham M, Meilhac S, Zaffran S . Building the mammalian heart from two sources of myocardial cells. Nat Rev Genet. 2005; 6(11):826-35. DOI: 10.1038/nrg1710. View