DNA methylation abnormalities of imprinted genes in congenital heart disease: a pilot study

Abstract

Background Congenital heart disease (CHD) is resulted from the interaction of genetic aberration and environmental factors. Imprinted genes, which are regulated by epigenetic modifications, are essential for the normal embryonic development. However, the role of imprinted genes in the etiology of CHD remains unclear. Methods After the samples were treated with bisulfate salt, imprinted genes methylation were measured by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. T test and One-way ANOVA were performed to evaluate the differences among groups. Odds ratios (ORs) were performed to evaluate the incidence risk of CHD in relation to methylation levels. Results We investigated the alterations of imprinted gene germline differential methylation regions (gDMRs) methylation in patients with CHD. Eighteen imprinted genes that are known to affect early embryonic development were selected and the methylation modification genes were detected by massarray in 27 CHD children and 28 healthy children. Altered gDMR methylation level of 8 imprinted genes was found, including 2 imprinted genes with hypermethylation of GRB10 and MEST and 6 genes with hypomethylation of PEG10, NAP1L5, INPP5F, PLAGL1, NESP and MEG3. Stratified analysis showed that the methylation degree of imprinted genes was different in different types of CHD. Risk analysis showed that 6 imprinted genes, except MEST and NAP1L5, within a specific methylation level range were the risk factors for CHD Conclusion Altered methylation of imprinted genes is associated with CHD and varies in different types of CHD. Further experiments are warranted to identify the methylation characteristics of imprinted genes in different types of CHD and clarify the etiologies of imprinted genes in CHD.

Imprinted Gene Expression and Function of the Dopa Decarboxylase Gene in the Developing Heart

“…The NHGRI-EBI Catalog of published genome-wide association studies does not currently report mutations in DDC that relate to heart development or cardiomyopathy. However, hypermethylation of the GRB10 ICR in peripheral blood samples has recently been associated with congenital heart disease ( Chang et al, 2021 ). The complex pattern of tissue-specific imprinted expression at this locus suggests it may warrant special consideration in genetic studies because Ddc_exon1a ablation has a mild effect on the developing heart and with a small effect size there could be moderately widespread ablation of this exon in human populations that presents a suitable genetic background for other mutations to cause developmental abnormalities.…”

Neonatal frontal-limbic connectivity is associated with externalizing behaviours in toddlers with Congenital Heart Disease

“…In critically ill children, early treatment with parenteral nutrition is associated with increased methylation and subsequent behavioral impairments 4 years post treatment ( Jacobs et al, 2021 ). Altered DNA methylation has been reported in neonates with CHD ( Cao et al, 2021 , Chang et al, 2021 ) although to our knowledge the effect of cardiac surgery has yet to be investigated. Earlier cardiac surgery or more severe neonatal illness may induce epigenetic changes associated with increased risk of internalizing symptoms in early childhood, however this hypothesis requires further investigation.…”

Epigenetics and Congenital Heart Diseases

“…Addition or removal of methyl groups to nucleotide regions by methylases and demethylases is an extremely dynamic and fine-tuned way of adjusting the accessibility of genic domains by impeding attachment of transcription factors or gene-expression protein complexes. Multiple studies have proven differential methylation, both at the genome-wide level and specific coding regions, in CHD-affected patients [ 28 , 29 , 30 ]. Even more specifically, different methylation patterns are observed within discordant monozygotic twins for tetralogy of Fallot and the double outlet right ventricle—although the global genome-wide methylation burden does not differ, specific promoters are highly divergent in CpG marking, and can be linked back to cardiac embryology (TBX20, NFATC1 involved in valve formation, GATA4, NKX2-5, NOTCH4) [ 31 , 32 ].…”