Profiling the role of m6A effectors in the regulation of pluripotent reprogramming

Author:

Wang Wenjun,Zhou Lei,Li Hui,Sun Tingge,Wen Xue,Li Wei,Esteban Miguel A.,Hoffman Andrew R.,Hu Ji-Fan,Cui Jiuwei

Abstract

AbstractThe N6-methyladenosine (m6A) RNA modification plays essential roles in multiple biological processes, including stem cell fate determination. To explore the role of the m6A modification in pluripotent reprogramming, we used RNA-seq to map m6A effectors in human iPSCs, fibroblasts, and H9 ESCs, as well as in mouse ESCs and fibroblasts. By integrating the human and mouse RNA-seq data, we found that 19 m6A effectors were significantly upregulated in reprogramming. Notably, IGF2BPs, particularly IGF2BP1, were among the most upregulated genes in pluripotent cells, while YTHDF3 had high levels of expression in fibroblasts. Using quantitative PCR and Western blot, we validated the pluripotency-associated elevation of IGF2BPs. Knockdown of IGF2BP1 induced the downregulation of stemness genes and exit from pluripotency. Proteome analysis of cells collected at both the beginning and terminal states of the reprogramming process revealed that the IGF2BP1 protein was positively correlated with stemness markers SOX2 and OCT4. The eCLIP-seq target analysis showed that IGF2BP1 interacted with the coding sequence (CDS) and 3’UTR regions of the SOX2 transcripts, in agreement with the location of m6A modifications. This study identifies IGF2BP1 as a vital pluripotency-associated m6A effector, providing new insight into the interplay between m6A epigenetic modifications and pluripotent reprogramming.

Funder

California Institute of Regenerative Medicine (CIRM) grant

Department of Veterans Affairs

Key Technologies Research and Development Program

the Innovative Program of National Natural Science Foundation of China

the National Natural Science Foundation of China

Fund of Jilin Provincial Finance Department

Fund of Jilin Provincial Development and Reform Commission

Fund of Jilin Provincial Health Commission

Publisher

Springer Science and Business Media LLC

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