Genetic impacts on DNA methylation: research findings and future perspectives

Villicaña, Sergio; Bell, Jordana T.

doi:10.1186/s13059-021-02347-6

Cited by 133 publications

(128 citation statements)

References 188 publications

(291 reference statements)

Supporting

Mentioning

107

Contrasting

Order By: Relevance

“…The effect of sex chromosome complement on autosomal DNA methylation in skeletal muscle has yet to be explored. Finally, genetic variants (copy number variants (CNVs) and single nucleotide polymorphisms (SNPs)) may affect DNA methylation status at specific loci [ 86 ], termed methylation-quantitative trait loci (meQTL). However, with the exception of a female bias for large, rare CNVs, there are no large sex differences in autosomal SNP minor allele frequencies [ 1 ].…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle methylome and transcriptome integration reveals profound sex differences related to muscle function and substrate metabolism

et al. 2021

View full text Add to dashboard Cite

Nearly all human complex traits and diseases exhibit some degree of sex differences, with epigenetics being one of the main contributing factors. Various tissues display sex differences in DNA methylation; however, this has not yet been explored in skeletal muscle, despite skeletal muscle being among the tissues with the most transcriptomic sex differences. For the first time, we investigated the effect of sex on autosomal DNA methylation in human skeletal muscle across three independent cohorts (Gene SMART, FUSION, and GSE38291) using a meta-analysis approach, totalling 369 human muscle samples (222 males and 147 females), and integrated this with known sex-biased transcriptomics. We found 10,240 differentially methylated regions (DMRs) at FDR < 0.005, 94% of which were hypomethylated in males, and gene set enrichment analysis revealed that differentially methylated genes were involved in muscle contraction and substrate metabolism. We then investigated biological factors underlying DNA methylation sex differences and found that circulating hormones were not associated with differential methylation at sex-biased DNA methylation loci; however, these sex-specific loci were enriched for binding sites of hormone-related transcription factors (with top TFs including androgen (AR), estrogen (ESR1), and glucocorticoid (NR3C1) receptors). Fibre type proportions were associated with differential methylation across the genome, as well as across 16% of sex-biased DNA methylation loci (FDR < 0.005). Integration of DNA methylomic results with transcriptomic data from the GTEx database and the FUSION cohort revealed 326 autosomal genes that display sex differences at both the epigenome and transcriptome levels. Importantly, transcriptional sex-biased genes were overrepresented among epigenetic sex-biased genes (p value = 4.6e−13), suggesting differential DNA methylation and gene expression between male and female muscle are functionally linked. Finally, we validated expression of three genes with large effect sizes (FOXO3A, ALDH1A1, and GGT7) in the Gene SMART cohort with qPCR. GGT7, involved in antioxidant metabolism, displays male-biased expression as well as lower methylation in males across the three cohorts. In conclusion, we uncovered 8420 genes that exhibit DNA methylation differences between males and females in human skeletal muscle that may modulate mechanisms controlling muscle metabolism and health.

show abstract

Section: Discussionmentioning

confidence: 99%

Skeletal muscle methylome and transcriptome integration reveals profound sex differences related to muscle function and substrate metabolism

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Several studies have mapped the interactions between genetic differences and variations in DNA methylation across numerous tissue and cell types (128)(129)(130)(131). The methylation quantitative trait loci showed that up to 48% of inter-individual variation in DNA methylation was related to CpG sites that were associated with nearby single nucleotide polymorphisms (SNPs) found in cis regulatory regions (132,133). SNPs located near or in CpG sites found in the promoter region of genes can either produce or remove CpG site methylation, leading to an alteration in the expression of the genes (Figure 2A).…”

Section: Candidate Host Gene Methylationmentioning

confidence: 99%

Deciphering DNA Methylation in HIV Infection

et al. 2021

View full text Add to dashboard Cite

With approximately 38 million people living with HIV/AIDS globally, and a further 1.5 million new global infections per year, it is imperative that we advance our understanding of all factors contributing to HIV infection. While most studies have focused on the influence of host genetic factors on HIV pathogenesis, epigenetic factors are gaining attention. Epigenetics involves alterations in gene expression without altering the DNA sequence. DNA methylation is a critical epigenetic mechanism that influences both viral and host factors. This review has five focal points, which examines (i) fluctuations in the expression of methylation modifying factors upon HIV infection (ii) the effect of DNA methylation on HIV viral genes and (iii) host genome (iv) inferences from other infectious and non-communicable diseases, we provide a list of HIV-associated host genes that are regulated by methylation in other disease models (v) the potential of DNA methylation as an epi-therapeutic strategy and biomarker. DNA methylation has also been shown to serve as a robust therapeutic strategy and precision medicine biomarker against diseases such as cancer and autoimmune conditions. Despite new drugs being discovered for HIV, drug resistance is a problem in high disease burden settings such as Sub-Saharan Africa. Furthermore, genetic therapies that are under investigation are irreversible and may have off target effects. Alternative therapies that are nongenetic are essential. In this review, we discuss the potential role of DNA methylation as a novel therapeutic intervention against HIV.

show abstract

“…Genetic variants can be associated with the methylation and expression level of the gene. These variants are known as the methylation quantitative trait locus (mQTL) (Villicaña & Bell, 2021) or expression quantitative trait locus (eQTL) (Degtyareva, Antontseva, & Merkulova, 2021).…”

Section: Introductionmentioning

confidence: 99%

Expression quantitative trait locus rs6356 is associated with the susceptibility of heroin addiction by potentially influencing the TH gene expression in the hippocampus and nucleus accumbens

Wang

Zhang³

et al. 2022

Preprint

View full text Add to dashboard Cite

Opioid addiction is a complicated and highly heritable brain disease. Dysfunction of dopaminergic signaling is involved in the pathogenesis of addictive disorders. Encoding the synthetase of dopamine, tyrosine hydroxylase (TH) gene has long been an interesting candidate in the genetic association studies for opioid addiction. However, the underlying mechanism of the association of risk gene variants and opioid addiction remains unknown. In the present study, we first analyzed the association between TH gene variants and susceptibility and traits of heroin addiction in 801 patients with heroin addiction and 930 healthy controls. The methylation level in the promoter region of the TH gene was detected and compared between the heroin addiction and healthy control groups. To reveal the potential mechanism of the association of TH gene variants and heroin addiction, correlation between the risk TH SNPs for heroin addiction and the methylation as well expression level of TH gene were examined. Our results demonstrated that SNP rs6356 was associated with the susceptibility of heroin addiction. CpG TH_15 was hypermethylated in the heroin addiction group compared with the healthy control group. Notably, SNP rs6356 was allele-specific correlated with the expression of TH gene in the hippocampus and nucleus accumbens, but not the methylation level of CpG TH_15. Our findings suggest that the eQTL rs6356 was associated with the risk of heroin addiction by potentially affecting the expression of TH gene in the mesocorticolimbic dopamine system brain regions including hippocampus and nucleus accumbens.

show abstract

Genetic impacts on DNA methylation: research findings and future perspectives

Cited by 133 publications

References 188 publications

Skeletal muscle methylome and transcriptome integration reveals profound sex differences related to muscle function and substrate metabolism

Skeletal muscle methylome and transcriptome integration reveals profound sex differences related to muscle function and substrate metabolism

Deciphering DNA Methylation in HIV Infection

Expression quantitative trait locus rs6356 is associated with the susceptibility of heroin addiction by potentially influencing the TH gene expression in the hippocampus and nucleus accumbens

Contact Info

Product

Resources

About