ASH1L contributes to oocyte apoptosis by regulating DNA damage

Abstract

In female mammals, the size of the initially established primordial follicle pool within the ovaries determines the reproductive lifespan of females. Interestingly, the establishment of the primordial follicle pool is accompanied by a remarkable programmed oocyte loss for unclear reasons. Here, we identify a new role of ASH1 like histone lysine methyltransferase (ASH1L) in controlling the apoptosis of oocytes during meiotic prophase I in mice. Our results showed that overexpression of Ash1l led to a dramatic loss of fetal oocytes via apoptosis, which subsequently resulted in a reduced capacity of the primordial follicle pool. Overexpression of Ash1l also led to a deficiency in DNA double-strand break repair associated with premature upregulation of TAp63 and p-CHK2, the major genome guardian of the female germline, following Ash1l overexpression in fetal ovaries. In summary, ASH1L was one of indispensible epigenetic molecules who acts as a guardian of the genome. It protects oocytes genome integrity and remove oocytes with seriously DNA damage by regulating the expression of TAp63 and p-CHK2 during meiotic prophase I in mice. Our study provides a perspective on the physiological regulatory role of DNA damage checkpoint signaling in fetal oocyte guardianship and female fertility.