METTL3-mediated m6A methylation regulates granulosa cells autophagy during follicular atresia in pig ovaries

Follicular atresia refers to the failure of a follicle to ovulate or rupture; this condition is considered physiologically normal in mammals. Throughout the reproductive life of human females, approximately 400 follicles will achieve ovulation and approximately 250,000 follicles are lost due to atresia [1]. The atresia of primordial follicles sustains the development of preponderant follicles to maintain the maturation of oocytes [2]. Follicular atresia is an apoptotic process regulated by hormones [3]. However, it is not exclusively controlled by apoptosis, and autophagy was found to be another regulatory mechanism [4].

During females birth, follicular atresia is mainly mediates oocyte autophagy [5]. Another study confirmed that a large number of increased autophagy characteristics are present in most dying oocytes [6]. Autophagy maintains the number of healthy primordial follicles, whereas excessive autophagy cell death affects the quality and number of oocytes [7]. In addition, granulosa cell (GC) autophagy is intimately associated with follicular atresia. The atresia of the preantral follicle occurs mainly through enhanced autophagy of GCs [8]. GC death induced by oxidative stress represents a commonly occurring cause of follicular atresia. Follicle-stimulating hormone (FSH) inhibited oxidative stress by resisting autophagy in GCs through FSH-FOXO1 signalling, indicating that follicular atresia may be induced by autophagy regulated by FSH [9]. In conclusion, these results suggest that autophagy plays an important role in follicular development and atresia.

N6-methyladenosine (m6A) is the most conserved, abundant and common RNA modification found in eukaryotic RNAs [10]. A growing number of studies have revealed the role of m6A modification in regulating autophagy. Fat mass and obesity-associated (FTO) protein is a demethylase that was found to positively regulate autophagy in an activity-dependent manner [11]. N6-methyladenosine (m6A)-binding protein YTHDF1 promoted hypoxia-induced autophagy by facilitating the translation of ATG2A and ATG14 [12]. Recent studies have shown that m6A methylation is involved in the control of oogenesis [13], oocyte Maturation [14], and embryonic development [15]. Notably, METTL3-mediated m6A methylation supported porcine blastocyst development by negatively modulating autophagy [16]. However, the role of m6A RNA methylation-mediated autophagy in follicular development and atresia has not been reported. We hypothesized that m6A methylation might regulate follicular atresia via affecting autophagy.

In this study, we verified the relationship between follicular atresia and GCs autophagy, follicular atresia and m6A modification. Then, the possible mechanism of m6A modification regulating GC autophagy was explored by transcriptome sequencing, overexpressing and knockdown of METTL3. Our findings provide novel insights to further toward understanding the mechanism of follicular atresia in mammals.

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