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

Chenxiang Xi; Jiatong Sun; Xiaocui Xu; You Wu; Xiaochen Kou; Yanhong Zhao; Jiacheng Shen; Yu Dong; Kang Chen; Zhongqu Su; Dan Liu; Wen Ye; Yingdong Liu; Ran Zhang; Yiliang Xu; Hong Wang; Lujiang Hao; Li Wu; Shaorong Gao

doi:10.1016/j.stemcr.2022.06.012

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

Stem Cell Reports. 2022 Aug 9;17(8):1799-1809. doi: 10.1016/j.stemcr.2022.06.012.

Authors

Chenxiang Xi¹, Jiatong Sun², Xiaocui Xu², You Wu², Xiaochen Kou³, Yanhong Zhao³, Jiacheng Shen², Yu Dong², Kang Chen², Zhongqu Su², Dan Liu², Wen Ye², Yingdong Liu², Ran Zhang⁴, Yiliang Xu², Hong Wang³, Lujiang Hao⁵, Li Wu⁶, Shaorong Gao⁷

Affiliations

¹ School of Bioengineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China.
² Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
³ Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
⁴ Anhui Toneker Biotechnology Co., Ltd., Jinzhai, Anhui 201615, China.
⁵ School of Bioengineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China. Electronic address: lujiang_hao@qlu.edu.cn.
⁶ Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. Electronic address: 14_wuli@tongji.edu.cn.
⁷ Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. Electronic address: gaoshaorong@tongji.edu.cn.

Abstract

The METTL3-METTL14 complex, the "writer" of N⁶-methyladenosine (m⁶A), plays an important role in many biological processes. Previous studies have shown that Mettl3 overexpression can increase the level of m⁶A 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 m⁶A-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 m⁶A-independent function of Mettl14 in reprogramming and provide new insight into the interplay between senescence and reprogramming in vitro.

Keywords: Mettl14; m(6)A methylation; reprogramming; senescence-associated secretory phenotype (SASP).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cellular Reprogramming* / genetics
Induced Pluripotent Stem Cells* / metabolism
Kruppel-Like Factor 4
Senescence-Associated Secretory Phenotype

Substances

Kruppel-Like Factor 4