DNA methylation changes in endometrium and correlation with gene expression during the transition from pre-receptive to receptive phase

Abstract

The inner uterine lining (endometrium) is a unique tissue going through remarkable changes each menstrual cycle. Endometrium has its characteristic DNA methylation profile, although not much is known about the endometrial methylome changes throughout the menstrual cycle. The impact of methylome changes on gene expression and thereby on the function of the tissue, including establishing receptivity to implanting embryo, is also unclear. Therefore, this study used genome-wide technologies to characterize the methylome and the correlation between DNA methylation and gene expression in endometrial biopsies collected from 17 healthy fertile-aged women from pre-receptive and receptive phase within one menstrual cycle. Our study showed that the overall methylome remains relatively stable during this stage of the menstrual cycle, with small-scale changes affecting 5% of the studied CpG sites (22,272 out of studied 437,022 CpGs, FDR < 0.05). Of differentially methylated CpG sites with the largest absolute changes in methylation level, approximately 30% correlated with gene expression measured by RNA sequencing, with negative correlations being more common in 5′ UTR and positive correlations in the gene ‘Body’ region. According to our results, extracellular matrix organization and immune response are the pathways most affected by methylation changes during the transition from pre-receptive to receptive phase.

Improved prediction of chronological age from DNA methylation limits it as a biomarker of ageing

“…A total of 319,607 probes (No Pruned Set) passed our quality control and 128,405 probes (Pruned Set) were retained after pruning based upon the pairwise correlation of probes (see next section). To test the performance of age predictors in non-blood tissues, we downloaded 13 cohorts from GEO database with accession ID GSE61431 (brain) 37 , GSE59685 (brain) 38 GSE80970 (brain), GSE101961 (breast) 39 , GSE108213 (breast), GSE48325 (liver) 40 , GSE61257 (adipose) 41 , GSE61258 (liver) 41 , GSE61259 (breast) 41 , GSE88883 (breast) 42 , GSE90060 (endometrium) 43 , GSE92767 (saliva) 44 , GSE99029 (saliva) 45…”

Mother and Embryo Cross-Communication

“…Aberrant DNA methylation of the CpG island in the promoter regions of ER or PR has been reported in endometrial carcinoma, suggesting regulation of the uterus by epigenetic mechanisms [95,96]. Factors related to endometrial receptivity, such as HOXA10 and MUC1 have also been shown to be controlled by hormone-dependent DNA methylation, which is associated with infertility [97,98], and changes in DNA methylation in the endometrium have been correlated with gene expression during the transition from the pre-receptive to receptive phase in humans [99,100]. Interestingly, comparison of changes in transcriptomes and corresponding DNA methylomes on the same samples revealed association of gene expression and DNA methylation for a number of loci related to endometrial biology [100], suggesting an interplay between hormones and the uterus at the level of the epigenome [101].…”

Epigenetic changes occur at decidualisation genes as a function of reproductive ageing in mice

“…Although it may be tempting to speculate that treatment with methylation inhibitors such as 5-azacytidine could prevent or reset some of these changes, the difficulty will be to direct them to the correct target loci. However, since DNA methylation changes also correlate with gene expression dynamics in the human endometrium during the endometrial cycle (Kukushkina et al, 2017), such ageinduced epigenomic rearrangements may be of significant importance for the decline in uterine function and fertility linked to advanced maternal age in humans.…”