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.
Highlights
DNA methylation is a type of epigenetic modification of post-replicative DNA, where a methyl residue is covalently added to the cytosine nucleotides
The endometrial function is believed to be under epigenetic control[5], less is known about how endometrial DNA methylation pattern changes throughout the menstrual cycle, what impact it has on gene expression, and whether aberrations in methylation pattern could lead to altered endometrial function
None of the previous studies have used genome-wide technologies to target directly the establishment of endometrial receptivity, we lack an understanding on how global DNA methylation changes and concomitant changes in gene expression occurring in a limited time-frame could contribute to controlling endometrial receptivity
Summary
DNA methylation is a type of epigenetic modification of post-replicative DNA, where a methyl residue is covalently added to the cytosine nucleotides. The endometrial methylome might be dynamic throughout the menstrual cycle[6, 7], correlate with changes in the transcriptome[6, 7] and play a role in the pathogenesis of endometrial disorders by affecting the expression of genes relevant for maintaining proper endometrial function[6, 8,9,10]. None of the previous studies have used genome-wide technologies to target directly the establishment of endometrial receptivity, we lack an understanding on how global DNA methylation changes and concomitant changes in gene expression occurring in a limited time-frame could contribute to controlling endometrial receptivity. Pathway analysis was used to put the findings into a wider biological context
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