Dataset Information

DNA methylation modulated genetic variant effect on gene transcriptional regulation.

ABSTRACT: Expression quantitative trait locus (eQTL) analysis has emerged as an important tool in elucidating the link between genetic variants and gene expression, thereby bridging the gap between risk SNPs and associated diseases. We recently identified and validated a specific case where the methylation of a CpG site influences the relationship between the genetic variant and gene expression. Here, to systematically evaluate this regulatory mechanism, we develop an extended eQTL mapping method, termed DNA methylation modulated eQTL (memo-eQTL). Applying this memo-eQTL mapping method to 128 normal prostate samples enables identification of 1063 memo-eQTLs, the majority of which are not recognized as conventional eQTLs in the same cohort. We observe that the methylation of the memo-eQTL CpG sites can either enhance or insulate the interaction between SNP and gene expression by altering CTCF-based chromatin 3D structure. This study demonstrates the prevalence of memo-eQTLs paving the way to identify novel causal genes for traits or diseases associated with genetic variations.

SUBMITTER: Zeng Y

PROVIDER: S-EPMC10709945 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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DNA methylation modulated genetic variant effect on gene transcriptional regulation.

Zeng Yong Y Jain Rahi R Lam Magnus M Ahmed Musaddeque M Guo Haiyang H Xu Wenjie W Zhong Yuan Y Wei Gong-Hong GH Xu Wei W He Housheng Hansen HH

Genome biology 20231208 1

<h4>Background</h4>Expression quantitative trait locus (eQTL) analysis has emerged as an important tool in elucidating the link between genetic variants and gene expression, thereby bridging the gap between risk SNPs and associated diseases. We recently identified and validated a specific case where the methylation of a CpG site influences the relationship between the genetic variant and gene expression.<h4>Results</h4>Here, to systematically evaluate this regulatory mechanism, we develop an ext ...[more]

PMID: 38066556

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Project description:BackgroundAcute chorioamnionitis (aCA), inflammation of the placenta and fetal membranes, is a frequently reported lesion in preterm deliveries. Genetic variants in innate immune system genes such as Interleukin-6 (IL6) may contribute to the placenta's inflammatory response, thus predisposing some pregnancies to aCA. These genetic variants may modulate molecular processes such as DNA methylation and gene expression, and in turn might affect susceptibility to aCA. Currently, there is remarkably little research on the role of fetal (placental) genetic variation in aCA. We aimed to explore the associations between genetic variants in candidate immune-system genes and susceptibility towards inflammatory responses in the placenta, which is linked to a strong inflammatory response in the newborn.MethodsDNA samples from 269 placentas (72 aCA cases, 197 non-aCA cases) were collected for this study. Samples were genotyped at 55 ancestry informative markers (AIMs) and 16 additional single nucleotide polymorphisms (SNPs) in 12 candidate innate immune system genes using the Sequenom iPLEX Gold Assay. Publicly available datasets were used to obtain DNA methylation (GSE100197, GSE74738, GSE115508, GSE44667, GSE98224) and gene expression data (GSE44711, GSE98224).ResultsDifferences in IL6 placental allele frequencies were associated with aCA (rs1800796, p = 0.04) with the CC genotype specifically implicated (OR = 3.1; p = 0.02). In a subset of the placental samples (n = 67; chorionic villi), we showed that the IL6 SNP (rs1800796) was associated with differential DNA methylation in five IL6-related CpG sites (cg01770232, cg02335517, cg07998387, cg13104385, and cg0526589), where individuals with a CC genotype showed higher DNA methylation levels than individuals carrying the GG genotype. Using two publicly available datasets, we observed that the DNA methylation levels at cg01770232 negatively correlated with IL6 gene expression in the placenta (r = - 0.67, p < 0.004; r = - 0.56, p < 2.937e-05).ConclusionsWe demonstrated that the minor C allele at the IL6 SNP (rs1800796), which is largely limited to East Asian populations, is associated with the presence of aCA. This SNP was associated with increased DNA methylation at a nearby MEPC2 binding site, which was also associated with decreased expression of IL6 in the placenta. Decreased expression of IL6 may increase vulnerability to microbial infection. Additional studies are required to confirm this association in Asian populations with larger sample sizes.

Dataset Information

DNA methylation modulated genetic variant effect on gene transcriptional regulation.

Publications

DNA methylation modulated genetic variant effect on gene transcriptional regulation.

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