Comparison of chromatin accessibility remodeling of granulosa cells in patients with endometrioma or pelvic/tubal infertility.

PURPOSE: To elucidatethe epigenetic alteration associated with impaired oogenesis in endometrioma using multi-omic approaches. METHODS: ATAC-seq was performed on the granulosa cells (GCs) of 6 patients (3 with endometrioma and 3 without). Follicular samples from another 20 patients (10 with endometrioma and 10 without) were collected for mRNA-seq analysis of GCs and extracellular vesicles (EVs) of follicular fluid. qRT-PCR validated candidate genes in GCs from 44 newly enrolled patients (19 with endometrioma and 25 without). mRNA abundance was compared with the Mann-Whitney test. Pearson's correlation analyzed relationships between candidate genes and oocyte parameters. RESULTS: Chromatin accessibility and gene expression profiles of GCs from endometrioma patients differed significantly from the pelvic/tubal infertility group. RNA-seq revealed most differentially expressed genes were downregulated (6216/7325) and enriched in the cellular localization pathway. Multi-omics analyses identified 22 significantly downregulated genes in the GCs of endometrioma patients, including PPIF (P < 0.0001) and VEGFA (P = 0.0148). Both genes were further confirmed by qRT-PCR. PPIF (r = 0.46, p = 0.043) and VEGFA (r = 0.45, p = 0.048) correlated with the total number of retrieved oocytes. CONCLUSIONS: GC chromatin remodeling may disrupt GC and EV transcriptomes, interfering with somatic cell-oocyte communication and leading to compromised oogenesis in endometrioma patients.