Mettl14-driven senescence-associated secretory phenotype facilitates somatic cell reprogramming

The METTL3-METTL14 complex, the “writer” of N(6)-methyladenosine (m(6)A), plays an important role in many biological processes. Previous studies have shown that Mettl3 overexpression can increase the level of m(6)A and promote somatic cell reprogramming. Here, we demonstrate that Mettl14, another component of the methyltransferase complex, can significantly enhance the generation of induced pluripotent stem cells (iPSCs) in an m(6)A-independent manner. In cooperation with Oct4, Sox2, Klf4, and c-Myc, overexpressed Mettl14 transiently promoted senescence-associated secretory phenotype (SASP) gene expression in non-reprogrammed cells in the late stage of reprogramming. Subsequently, we demonstrated that interleukin-6 (IL-6), a component of the SASP, significantly enhanced somatic cell reprogramming. In contrast, blocking the SASP using a senolytic agent or a nuclear factor κB (NF-κB) inhibitor impaired the effect of Mettl14 on reprogramming. Our results highlight the m(6)A-independent function of Mettl14 in reprogramming and provide new insight into the interplay between senescence and reprogramming in vitro.