Genetic regulation of methylation in human endometrium and blood and gene targets for reproductive diseases

Abstract

BackgroundMajor challenges in understanding the functional consequences of genetic risk factors for human disease are which tissues and cell types are affected and the limited availability of suitable tissue. The aim of this study was to evaluate tissue-specific genotype-epigenetic characteristics in DNA samples from both endometrium and blood collected from women at different stages of the menstrual cycle and relate results to genetic risk factors for reproductive traits and diseases.ResultsWe analysed DNA methylation (DNAm) data from endometrium and blood samples from 66 European women. Methylation profiles were compared between stages of the menstrual cycle, and changes in methylation overlaid with changes in transcription and genotypes. We observed large changes in methylation (27,262 DNAm probes) across the menstrual cycle in endometrium that were not observed in blood. Individual genotype data was tested for association with methylation at 443,016 and 443,101 DNAm probes in endometrium and blood respectively to identify methylation quantitative trait loci (mQTLs). A total of 4546 sentinel cis-mQTLs (P < 1.13 × 10−10) and 434 sentinel trans-mQTLs (P < 2.29 × 10−12) were detected in endometrium and 6615 sentinel cis-mQTLs (P < 1.13 × 10−10) and 590 sentinel trans-mQTLs (P < 2.29 × 10−12) were detected in blood. Following secondary analyses, conducted to test for overlap between mQTLs in the two tissues, we found that 62% of endometrial cis-mQTLs were also observed in blood and the genetic effects between tissues were highly correlated. A number of mQTL SNPs were associated with reproductive traits and diseases, including one mQTL located in a known risk region for endometriosis (near GREB1).ConclusionsWe report novel findings characterising genetic regulation of methylation in endometrium and the association of endometrial mQTLs with endometriosis risk and other reproductive traits and diseases. The high correlation of genetic effects between tissues highlights the potential to exploit the power of large mQTL datasets in endometrial research and identify target genes for functional studies. However, tissue-specific methylation profiles and genetic effects also highlight the importance of also using disease-relevant tissues when investigating molecular mechanisms of disease risk.Electronic supplementary materialThe online version of this article (10.1186/s13148-019-0648-7) contains supplementary material, which is available to authorized users.

Cellular Origins of Endometriosis: Towards Novel Diagnostics and Therapeutics

“…There is genetic regulation of methylation signals in the endometrium and altered methylation signals are located in regions of endometriosis risk (GREB, C11orf46, NR2C1, KDR, WNT4) identified from the genome-wide association studies (GWAS). 63 As such, alterations in genomic regulation have the potential to affect cellular behavior and the physiological mechanism and developmental context of cells initiating endometriosis lesions (►Fig. 1b).…”

Genetic Regulation of Physiological Reproductive Lifespan and Female Fertility

“…It is thought that the causal variants are mostly located in genome sequences responsible for regulating epigenetic programming and gene expression, and influence disease risk through modifying this regulation. Numerous studies now document the genetic regulation of both gene expression [ 55 , 81 , 82 ] and methylation signals [ 85 , 86 ].…”

The role of epigenetic mechanisms in the regulation of gene expression in the cyclical endometrium

“…DNA methylation profile has been correlated with its biological age, and changes in this profile have been associated with abnormal function of the endometrium [ 78 ]. The variation in DNA methylation content across the menstrual cycle is tissue-specific as the methylation state of endometrial tissue changes according to the endometrial phase; in contrast, this is not observed in blood samples [ 79 ]. This suggests that DNA methylation regulates gene expression in a tissue-specific manner during the endometrial cycle.…”

“…This suggests that the dynamics of DNA methylation in the endometrium are regulated in part by the hormone milieu, which can influence the function of this tissue by modulating its transcriptome. Recent studies have identified several endometrial phase-dependent changes in the DNA methylation content of genes regulated by estrogens or progesterone throughout the endometrial cycle [ 79 , 86 ]. Moreover, estradiol, progesterone, or the combination of both modifies the DNA methylome of primary cultures of stromal cells in a hormone-specific manner, with estradiol inducing the most extensive changes [ 86 ].…”

“…In a study conducted by Mortlock et al [ 79 ], a methylation quantitative trait loci (mQTL) analysis was performed to identify the relationship between SNPs associated with pathologies of the endometrium (e.g., endometriosis) and DNA methylation. In this study, an association between specific SNPs and DNA methylation was found in blood samples and endometrium, suggesting mQTLs as potential biomarkers for endometrial pathologies.…”