O-105 Chromatin accessibility of oocytes contributes to PCOS transgenerational inheritance

Abstract Study question What is the underlying mechanism contributing to the transgenerational defects of oocytes and embryos of polycystic ovary syndrome (PCOS)? Summary answer The transgenerational inheritance of abnormal chromatin accessibility in the PCOS oocytes is responsible for the defect of oocytes and embryos in transgeneration. What is known already Studies have provided evidence of compromised oocyte quality and related adverse impacts. Observed PCOS animal-model oocyte defects include meiotic abnormalities, mitochondrial dysfunction, and increased oxidative stress. Elevated androgen levels are associated with reduced fertilization rates and lower cleavage rates during in vitro fertilization (IVF) treatment. PCOS could be transgenerationally transmitted, and unique altered gene expression has been observed in metaphase II (MII) oocytes from all offspring in PCOS mice. Study design, size, duration We profiled the transcriptome and chromatin accessibility of oocytes and preimplantation embryos in F0-F2 offspring of PCOS mice, to explored whether the inheritance of chromatin accessibility defects in PCOS oocytes was responsible for the abnormalities of oocytes and embryos in PCOS offspring. Besides, oocytes from 13 healthy women and 8 women with PCOS, 24 blood samples from 24 women with/without PCOS were analyzed to validate the molecular mechanisms of PCOS inheritance. Duration: 2019.5∼2022.12. Participants/materials, setting, methods PCOS mice models were established by means of DHEA-exposure. Smart-seq2 and DNase-seq were utilized to investigate the transcriptome and chromatin accessibility of oocytes and preimplantation embryos in F0-F2 offspring of PCOS mice. Bioinformatic analysis was applied to explore the differential gene expression and chromatin accessibility of oocytes and embryos in PCOS mice and offspring comparing to controls. Common gene signatures in the tissues of PCOS women and PCOS daughters are analyzed compared to control samples. Main results and the role of chance In PCOS mice, we observed transcriptional alteration in oocytes and 2-cell embryos compared to normal mice. There are 4229 and 1197 differentially expressed genes (DEGs) in PCOS oocytes and 2-cell embryos. The DEGs includes both maternal factors and zygotic genome activation (ZGA) genes. Interestingly, in PCOS 2-cell embryos, we observed hundreds of pre-activated genes which are silence in normal 2-cell embryo but expressed in PCOS 2-cell embryos. Notably, many DEGs in the oocytes of PCOS mice were also differentially expressed in the oocytes of F2 PCOS mice compared to control mice, supporting the transgenerational inheritance of transcriptional alteration in PCOS oocytes. Mechanismly, the changes of chromatin accessibility were associated with the DEGs in PCOS oocytes and embryos. In particular, chromatin accessibility of the pre-activated gene promoters is elevated in PCOS oocytes compared to that in normal oocytes. Furthermore, many of the abnormal chromatin accessibility signals detected in F0 PCOS oocytes were also observed in F2 PCOS oocytes. Finally, our data showed that some DEGs in the oocytes of PCOS mice were also differentially expressed in human PCOS oocytes compared to the control oocytes. Common genes identified in PCOS offspring may be used as potential predictors of PCOS phenotype. Limitations, reasons for caution Which factors contribute to the abnormalities of chromatin accessibility in PCOS oocytes are still unknown. Wider implications of the findings The candidate genes may be used as potential predictors of PCOS phenotype and provide the clues for PCOS offspring . Trial registration number not applicable