The N6-methyladenosine landscape of ovarian development and aging highlights the regulation by RNA stability and chromatin state

Abstract

The versatile epigenetic modification known as N6-methyladenosine (m⁶A) has been demonstrated to be pivotal in numerous physiological and pathological contexts. Nonetheless, the precise regulatory mechanisms linking m⁶A to histone modifications and the involvement of transposable elements (TEs) in ovarian development and aging are still not completely understood. First, we discovered that m⁶A modifications are highly expressed during ovarian aging (OA), with significant contributions from decreased m⁶A demethylase FTO and overexpressed m⁶A methyltransferase METTL16. Then, using FTO knockout mouse model and KGN cell line, we also observed that FTO deletion and METTL16 overexpression significantly increased m⁶A levels. This led to the downregulation of the methyltransferase SUV39H1, resulting in reduced H3K9me3 expression. The downregulation of SUV39H1 and H3K9me3 primarily activated LTR7 and LTR12, subsequently activating ERV1. This resulted in a decrease in cell proliferation, while the levels of apoptosis, cellular aging markers, and autophagy markers significantly increased in OA. In summary, our study offers intriguing insights into the role of m⁶A in regulating DNA epigenetics, including H3K9me3 and TEs, as well as autophagy, thereby accelerating OA.