Dysregulated epigenetic memory in early embryos offers new clues to the inheritance of PCOS: Study
Novel research presented today at the 41st Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE) has found that embryos from women with polycystic ovary syndrome (PCOS) carry a distinctive ‘epigenetic memory’ that could explain why the condition often runs in families.
PCOS is a common hormonal disorder affecting an estimated 1 in 10 women of reproductive age worldwide. It is characterised by irregular menstrual cycles, excess levels of androgens (male hormones) and the presence of multiple cysts on the ovaries. While it is recognised as a leading cause of infertility, the exact causes and mechanisms of inheritance remain unclear.
The study, led by Dr. Qianshu Zhu, analysed oocytes and pre-implantation embryos from 133 PCOS patients and 95 non-PCOS infertile women undergoing fertility treatment. The team used ultra-low-input sequencing to analyse both gene activity and epigenetic changes – chemical tags that regulate how genes turn on and off without altering the underlying DNA sequence.
The research revealed widespread disruptions in the activity of genes responsible for early embryonic genome activation, metabolic processes, epigenetic regulation, and chromatin structure in embryos from women with PCOS. These disruptions also affected retrotransposons – mobile DNA elements usually tightly regulated to maintain genomic stability – further highlighting how early developmental programming is affected.
These abnormalities were closely linked to irregular patterns of three histone marks that play a key role in controlling gene expression: H3K27me3, H3K4me3 and H3K9me3.
“Importantly, about half of the abnormal H3K27me3 signatures we saw in Day 3 embryos were already present in the oocyte”, said Dr. Zhu. “This tells us that an epigenetic signal is being passed from mother to embryo before implantation even begins.”
Treating affected embryos in vitro with two PRC2 inhibitors (EED226 and valemetostat) reduced abnormal H3K27me3 levels and partially restored normal gene activity, suggesting a potential therapeutic avenue for correcting epigenetic imbalances.
“We were surprised to find that H3K27me3, which is a histone mark best known in cancer biology, could also be an inherited driver of PCOS”, Dr. Zhu noted. “It opens a new window for embryo assessment and perhaps even intervention.”
Currently, PCOS diagnostics focus on hormone levels and ovarian morphology. Epigenetic profiling, particularly of H3K27me3, could eventually complement these tools, offering earlier risk assessment for offspring conceived by affected mothers. In assisted reproductive technologies (ART), H3K27me3 patterns may even serve as biomarkers for embryo selection during IVF, potentially improving the success of fertility treatments.
Dr. Zhu cautioned that the work is based on laboratory-grown embryos and does not yet prove long-term effects in children. The team’s next step is to validate the findings in mouse models by knocking down the Kdm6a and Kdm6b genes, which remove H3K27me3, to investigate whether offspring develop PCOS-like traits.
“If we confirm that altering these histone marks changes PCOS traits in the next generation, we’ll have a powerful target for prevention”, he said.
Prof. Dr. Karen Sermon, Chair of ESHRE, commented, “PCOS remains largely unsolved as to the molecular origins of the disease, and these findings on a large number of oocytes and embryos from affected women open a new avenue for its understanding and even treatment.”
Reference:
Dysregulated epigenetic memory in early embryos offers new clues to the inheritance of polycystic ovary syndrome (PCOS), European Society of Human Reproduction and Embryology, Meeting: ESHRE 41st Annual Meeting.
