Aberrant DNA methylation profiling affecting the endometrial receptivity in recurrent implantation failure patients undergoing in vitro fertilization.

Abstract

DNA methylation profile in mid-secretory phase of endometrium is reported to be varied from other phases in natural menstrual cycle. Therefore, we intended to study the impairment in endometrial receptivity by performing whole-genome methylation and gene expression profiling in endometrium of recurrent implantation failure patients (RIF) during IVF under controlled ovarian stimulation (COS). Endometrial biopsies were collected from IVF-RIF patients (cases, n=6) and healthy fertile oocyte donors (controls, n=6) undergoing COS after 6/7th day of human chorionic gonadotropin administration. The whole-genome methylation and gene expression microarray were performed and analysed by GenomeStudio software (P<.05 by Illumina Custom Model), whereas the enrichment analysis was performed using "Database for Annotation, Visualization and Integrated Discovery" (DAVID, V6.8). Significant differentially methylated genes were correlated with dys-regulated genes using Pearson's correlation. Differential methylation in RIF patients revealed 448 CpG sites. The enrichment analysis showed aberrant methylation in genes involved in immunological response and G protein activity. Methylation in NLRP2 gene in inflammatory pathway had significant negative correlation with gene expression (P=.008), whereas SERPINA5 gene that is already known to be involved in endometrial receptivity was observed to be hypomethylated in promoter region with highest delta beta value and up-regulated in gene expression analysis. The aberrant methylation of genes involved in immunological functions and G protein activation was found to be prevalent which might suggest a role in endometrial receptivity. However, the findings need to be further validated on a larger cohort of IVF-RIF patients.