The biological clock is ticking- age related fertility loss in women in an epigenetic view

As we age, heterochromatin shifts and re-distributes around the genome, changing its epigenetic landscape. This phenomenon is commonly described as "epigenetic aging". Oocytes aging is characterized by non-disjunction of chromosomes and non-viable eggs. One possible mechanism for this early aging is related to the loss of Cohesin from the chromosomes, which is not re-loaded during adulthood. We hypothesize that epigenetic aging contributes to the process of Cohesin loss and meiotic dysfunction. In order to establish that heterochromatin is lost with age in oocytes, we used mouse oocytes. We immuno-stained oocytes for heterochromatin markers and compared young and old females for the staining pattern. In addition, we used surplus human GV oocytes from the IVF clinic and correlated maternal age with the heterochromatin staining. In all cases studied- both in mouse and human, heterochromatin stained significantly weaker in older females, for different heterochromatin related histone modification (H3k9me, H4k20me, H3k27me). In human oocytes we also observed reduction in DNA methylation (5mc). These results show that a reduction in heterochromatin levels indeed occurs with age in oocytes. To examine whether Cohesin loss is an upstream event to heterochromatin loss we used a transgenic mouse model, and removed all meiotic Cohesin from young oocytes. We then immune-stained these oocytes for heterochromatin markers, to see if Cohesin loss caused heterochromatin loss. From our results, it seems that Cohesin removal does not reduce heterochromatin in the oocyte, but in fact the opposite is true. These results suggest that Cohesin loss is not the cause for heterochromatin loss in oocytes. We will also present results showing the oocyte epigenome integrates internal signals such as age and signals form the environment such as diet and hormones. To conclude, epigenetic aging greatly affects oocytes, and is involved in oocyte chromosome non-disjunction- a primary cause for age related fertility loss.