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Journal of Genetics

, 98:110 | Cite as

Hypermethylation of NRG1 gene correlates with the presence of heart defects in Down’s syndrome

  • Artur Dobosz
  • Agnieszka Grabowska
  • Miroslaw Bik-MultanowskiEmail author
Research Article
  • 35 Downloads

Abstract

Congenital heart defects can decrease the quality of life and life expectancy in affected individuals, and constitute a major burden for the health care systems. Endocardial cushion defects are among the most prevalent heart malformations in the general population, and are extremely frequent (approximately a 100-fold higher prevalence) in children with Down syndrome. Several genes have been proposed to be involved in the pathogenesis of these malformations, but no common pathogenic DNA variants have been identified so far. Here, we focussed on constitutive, epigenetic alterations of function of selected genes, potentially important for endocardial cushion development. We used two types of microarrays, dedicated for assessment of gene promoter methylation and whole genome expression. First, we compared the gene promoter methylation profiles between two groups of Down syndrome patients, with and without heart defects of endocardial cushion-type. Then, to determine the functional role of the detected methylation alterations, we assessed the expression of the genes of interest. We detected significant hypermethylation of the NRG1 gene promoter region in children with heart defects. NRG1 is a key factor in maturation of endocardial cushions. Supplementary gene expression assessment revealed significantly decreased activity of the ERBB3, SHC3 and SHC4 genes in children with heart defects. The above three genes are closely related to the NRG1 gene and are crucial elements of the NRG/ErbB pathway. The results of this pilot study show that hypermethylation of the NRG1 gene promoter can reflect the functional genome alteration contributing to development of congenital heart defects of endocardial cushion-type.

Keywords

epigenetic microarray endocardial cushion defect trisomy 21. 

Supplementary material

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Supplementary material 1 (XLSX 63 kb)
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Supplementary material 2 (XLSX 81 kb)
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Supplementary material 3 (XLSX 11263 kb)

References

  1. Bik-Multanowski M., Revhaug C., Grabowska A., Dobosz A., Madetko-Talowska A., Zasada M. et al. 2018 Hyperoxia induces epigenetic changes in newborn mice lungs. Free Radic. Biol. Med. 121, 51–56.CrossRefGoogle Scholar
  2. Dobosz A. and Bik-Multanowski M. 2019 Long-term trends in prevalence of congenital heart defects in patients with Down syndrome in southern Poland. Dev. Period Med. 23, 184–189.Google Scholar
  3. Erickson S. L., O’Shea K. S., Ghaboosi N., Loverro L., Frantz G., Bauer M. et al. 1997 ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2- and heregulin-deficient mice. Development 124, 4999–5011.Google Scholar
  4. Gallou-Kabani C. and Junien C. 2005 Nutritional epigenomics of metabolic syndrome: new perspective against the epidemic. Diabetes 54, 1899–1906.CrossRefGoogle Scholar
  5. Gitler A. D., Lu M. M., Jiang Y. Q., Epstein J. A. and Gruber P. J. 2003 Molecular markers of cardiac endocardial cushion development. Dev. Dyn. 228, 643–650.CrossRefGoogle Scholar
  6. Henneman P., Bouman A., Mul A., Knegt L., van der Kevie-Kersemaekers A. M., Zwaveling-Soonawala N. et al. 2018 Widespread domain-like perturbations of DNA methylation in whole blood of Down syndrome neonates. PLoS One 13, e0194938.CrossRefGoogle Scholar
  7. Huang D. W., Sherman B. T. and Lempicki R. A. 2009 Systematic and integrative analysis of large gene lists using DAVID Bioinformatics Resources. Nat. Protoc. 4, 44–57.CrossRefGoogle Scholar
  8. Johnson W. E., Li W., Meyer C. A., Gottardo R., Carroll J. S., Brown M. et al. 2006 Model-based analysis of tiling-arrays for ChIP-chip. Proc. Natl. Acad. Sci. USA 103, 12457–12462.CrossRefGoogle Scholar
  9. Laursen H. B. 1976 Congenital heart disease in Down’s syndrome. Br. Heart J. 38, 32–38.CrossRefGoogle Scholar
  10. Lu J., Mccarter M., Lian G., Esposito G., Capoccia E., Delli-Bovi L. C. et al. 2016 Global hypermethylation in fetal cortex of Down syndrome due to DNMT3L overexpression. Hum. Mol. Genet. 25, 1714–1727.CrossRefGoogle Scholar
  11. Markwald R. R., Fitzharris T. P. and Smith W. N. 1975 Structural analysis of endocardial cytodifferentiation. Dev. Biol. 42, 160–180.CrossRefGoogle Scholar
  12. Meyer D. and Birchmeier C. 1995 Multiple essential functions of neuregulin in development. Nature 378, 386–390.CrossRefGoogle Scholar
  13. Mizuta K., Sakabe M., Hashimoto A., Ioka T., Sakai C., Okumura K. et al. 2015 Impairment of endothelial-mesenchymal transformation during atrioventricular cushion formation in tmem100 null embryos. Dev. Dyn. 244, 31–42.CrossRefGoogle Scholar
  14. Perera F. and Herbstman J. 2011 Prenatal environmental exposures, epigenetics, and disease. Reprod. Toxicol. 31, 363–373.CrossRefGoogle Scholar
  15. Rupert C. E. and Coulombe K. L. 2015 The roles of neuregulin-1 in cardiac development, homeostasis, and disease. Biomark. Insights 10 (suppl 1), 1–9.PubMedPubMedCentralGoogle Scholar
  16. Schenkel L. C., Rodenhiser D., Siu V., McCready E., Ainsworth P. and Sadikovic B. 2017 Constitutional epi/genetic conditions: genetic, epigenetic, and environmental factors. J. Pediatr. Genet. 6, 30–41.CrossRefGoogle Scholar
  17. Weber M., Davies J. J., Wittig D., Oakeley E. J., Haase M., Lam W. L. et al. 2005 Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat. Genet. 37, 853–862.CrossRefGoogle Scholar

Copyright information

© Indian Academy of Sciences 2019

Authors and Affiliations

  1. 1.Department of Medical Genetics, Faculty of MedicineJagiellonian University Medical CollegeKrakowPoland

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