N⁶-methyladenosine (m⁶A) is one of the most common and abundant modifications on mRNA molecules in eukaryotes. The formation of m⁶A is catalyzed by a multi-component methyltransferase complex containing METTL3/METTL14/WTAP. And m⁶A can be removed by two RNA demethylases, FTO and ALKBH5. The presence of m⁶A may affect the expression level, translation efficiency, nuclear retention, splicing, and stability of mRNAs. Deficiency of m⁶A formation has been proven to affect circadian rhythm, cell meiosis, and ESC proliferation, and thus it is implicated in obesity, cancer, and other human diseases. However, the regulatory mechanisms of m⁶A formation and the function of m⁶A in regulating cell reprogramming are still largely unknown.

 

 

To study this, Prof. WANG Xiu-Jie’s group from the Institute of Genetics and Developmental Biology, collaborated with Prof. ZHOU Qi’s group from the Institute of Zoology, and Prof. YANG Yungui’s group from Beijing Institute of Genomics, all belong to Chinese Academy of Sciences, discovered that m⁶A is regulated by microRNAs and promotes reprogramming to pluripotency. This work has been published online on Cell Stem Cell on Feb 12, 2015 and can be accessed at http://dx.doi.org/10.1016/j.stem.2015.01.016.

 

 

The work profiled the transcriptome-wide distribution of m⁶A modification in embryonic stem cells (ESC), induced pluripotent stem cells (iPSC), neural stem cells (NSC) and sertoli cells (SC), revealed dynamic m⁶A distribution along cell type specifically and stably expressed genes among four types of cells with different degrees of pluripotency. Further analysis found that motifs enriched at m⁶A peaks were reversely complementary to the seed sequences (5’ 2-8 nt) of miRNAs. A series of molecular cell biology experiments show that miRNAs can promote m⁶A generation in a sequence pairing manner at their targeting regions by recruiting METTL3 binding. In addition, increased m⁶A levels promote fibroblasts reprogramming to iPSCs.

 

 

Their results reveal a brand new function of miRNAs in regulating m⁶A generation and the important roles of m⁶A in promoting reprogramming process, and shed new lights on illustrating site-specific generation of m⁶A, miRNA’s function and somatic cell reprogramming.

 

 

This research was supported by grants from National Basic Research Program of Ministry of Science of China, Stem Cell and Regeneration Medicine Strategic Priority Research Program of the Chinese Academy of Sciences, and National Natural Science Foundation of China.

 

 

 

 

Figure. The site-specific selective mechanism of m⁶A formation and the function of m⁶A in regulating cell reprogramming. (Image by CHEN Tong, et al)