By combining their complementary expertise within RNA m6A modification, stem cell biology and bioinformatics, the lab of Prof. YANG Yungui from Beijing Institute of Genomics, Chinese Academy of Sciences (CAS), in collaboration with Prof. ZHOU Qi from Institute of Zoology, CAS and Prof. WANG Xiujie from Institute of Genetics and Developmental Biology, CAS, revealed that m6A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency, published online in Cell Stem Cell on February 12, 2015, selected as the Cover Story of Cell Stem Cell volume 16 issue 3 scheduled on March 5, 2015.

N6-methyl-adenosine (m6A) is one of the most common and abundant modifications on RNA molecules present in eukaryotes. Epitranscriptomic m6A methylation is catalyzed by a multicomponent methytransferase complex composed of at least three subunits: METTL3, METTL14 and WTAP, removed by demethylases FTO and ALKBH5, and recognized by cytoplasmic YTHDF2. m6A may mediate mRNA splicing in the nucleus and stability in the cytoplasm. However, molecular mechanisms underlying mRNA m6A site selectivity and its biological significance remain largely unknown.

Their current collaborative study reports m6A modification profiles in the mRNA transcriptomes of four cell types with different degrees of pluripotency. Comparative analysis reveals several new features of m6A, especially gene- and cell type-specific m6A mRNA modifications. They also show that microRNAs (miRNAs) regulate m6A modification via a sequence pairing mechanism. Manipulation of miRNA expression or sequences alters m6A modification levels, through modulating the binding of METTL3 methyltransferase to mRNAs containing miRNA targeting sites. Increased m6A abundance promotes the reprogramming of mouse embryonic fibroblasts (MEFs); conversely, reduced m6A levels impede reprogramming. Their results therefore uncover a role for miRNAs in regulating m6A formation of mRNAs, and provide a foundation for future studies of the functional role of m6A modification in cell reprogramming.

These findings revealed a brand new role of miRNAs in regulating mRNA epitranscriptomic modification in eukaryotes. Their findings on the functions of m6A in cell reprogramming also suggested that modulating m6A may serve as a new strategy to regulate cell reprogramming.

This research is supported by CAS Strategic Priority Research Programs, Ministry of Science and Technology, Natural Science Foundation of China.

RNA N6-Methyladenosine (m6A) is regulated by microRNAs and promotes reprogramming to pluripotency

（Image by Cheng Tong ）