m6A RNA Methylation Is Regulated by MicroRNAs and Promotes Reprogramming to Pluripotency

Abstract

N(6)-methyladenosine (m(6)A) has been recently identified as a conserved epitranscriptomic modification of eukaryotic mRNAs, but its features, regulatory mechanisms, and functions in cell reprogramming are largely unknown. Here, we report m(6)A modification profiles in the mRNA transcriptomes of four cell types with different degrees of pluripotency. Comparative analysis reveals several features of m(6)A, especially gene- and cell-type-specific m(6)A mRNA modifications. We also show that microRNAs (miRNAs) regulate m(6)A modification via a sequence pairing mechanism. Manipulation of miRNA expression or sequences alters m(6)A modification levels through modulating the binding of METTL3 methyltransferase to mRNAs containing miRNA targeting sites. Increased m(6)A abundance promotes the reprogramming of mouse embryonic fibroblasts (MEFs) to pluripotent stem cells; conversely, reduced m(6)A levels impede reprogramming. Our results therefore uncover a role for miRNAs in regulating m(6)A formation of mRNAs and provide a foundation for future functional studies of m(6)A modification in cell reprogramming.

An epigenetic view of developmental diseases: new targets, new therapies

“…[50] This study also reveals that m6A modification is required for the reprogramming, and can increase the reprogramming effi ciency. [50] Several genome wide association studies indicated an association between FTO gene and childhood and adult obesity. [51,52] The Over-expression of Fto increases food intake and results in obesity in mice; the mutation of Fto leads to postnatal growth retardation, signifi cant reduction in adipose tissue, lean body mass, and protects mice from obesity.…”

“…[49] Another interesting study has found that m6A modification enriched at miRNA target sites, and the formation of m6A depends on Dicer, a processor of miRNA maturation. [50] The modulation of miRNAs could affect the binding of Mettl3 to mRNA, and thus affect the abundance of m6A. [50] This study also reveals that m6A modification is required for the reprogramming, and can increase the reprogramming effi ciency.…”

“…[50] The modulation of miRNAs could affect the binding of Mettl3 to mRNA, and thus affect the abundance of m6A. [50] This study also reveals that m6A modification is required for the reprogramming, and can increase the reprogramming effi ciency. [50] Several genome wide association studies indicated an association between FTO gene and childhood and adult obesity.…”

Improving N6-methyladenosine site prediction with heuristic selection of nucleotide physical–chemical properties

“…(25) and (26)), although they are heavily affected by feature representations. For example, 7 physical-chemical properties, i.e., 3 PC , 11 PC , 9 PC , 12 PC , 10 PC , 13 PC , and 21 PC are ranked among the top 11 properties in both PseDNC and AC+CC based partial order relationships. Similarly, 7 common properties, i.e., 4 PC , 5 PC , 20 PC , 1 PC , 6 PC , 17 PC , and 7 PC , appear in the last 11 properties in both partial order relationships.…”

“…N 6 -methyladenosine (m 6 A) is one of the most prevalent post-transcriptional RNA modifications [1][2][3] and plays a critical role in a number of biological processes, including mRNA splicing, export, stability, immune tolerance and transcription [4][5][6][7][8][9][10]. Current researches revealed that the m 6 A modification is a dynamic and reversible process which affected the gene regulation function in apoptosis, circadian rhythm and meiosis [11][12][13][14][15].…”