Hypoxia induced ALKBH5 prevents spontaneous abortion by mediating m6A-demethylation of SMAD1/5 mRNAs

The molecules induced by hypoxia have been supposed to be important regulators of first trimester trophoblast activity, but the key mechanism mediating invasion of trophoblast cells is not fully illustrated. Here, we found that the expression of RNA demethylase ALKBH5 was upregulated in trophoblast upon hypoxia treatment and decreased in extravillous trophoblast (EVT) of patients with recurrent spontaneous abortion (RSA). Furthermore, we found that trophoblast-specific knockdown of ALKBH5 in mouse placenta suppressed the invasion of trophoblast and significantly led to fetus abortion in vivo. Then ALKBH5 was identified to promote the invasion of trophoblast. Mechanistically, we identified transcripts with altered methylation in trophoblast induced by hypoxia via m6A-seq, ALKBH5 translocated from nucleus to cytoplasm upon hypoxia treatment and demethylated certain target transcripts, such as m6A-modified SMAD1/SMAD5, consequently enhanced the translation of SMAD1/SMAD5 and then promoted MMP9 and ITGA1 production. Thus, we demonstrated that ALKBH5 promoted the activity of trophoblasts by enhancing SMAD1/5 expression via erasing their m6A modifications. Our research revealed a new m6A epigenetic way to regulate the invasion of trophoblast, which suggested a novel potential therapeutic target for spontaneous abortion prevention.