Over 100 different types of RNA modifications have been re-identified genome-wide in transcriptomes. Among them, adenosine-to-inosine (A-to-I) and N6-methyladenosines (m6A) are two of the most abundant RNA modifications, and both occur on A bases.
A-to-I and m6A have distinct catalytic modification mechanisms that A-to-I conversion is catalyzed by adenosine deaminases acting on RNA (ADARs) that preferentially bind to double-stranded RNA substrates, while m6A is reversibly processed by a different set of enzymes and mainly occurs in single-stranded RNA regions. The different sequence and structure features for A-to-I or m6A suggest that they are not likely to compete for the same A bases. However, whether m6A and A-to-I are always independently regulated is unanswered.
The research groups led by Dr. YANG Li at CAS-MPG Partner Institute for Computational Biology of Chinese Academy of Sciences (CAS) and Dr. CHEN Lingling at Shanghai Institute of Biochemistry and Cell Biology of CAS demonstrated a previously under-appreciated interplay between m6A modification and A-to-I editing, highlighting a complex epitranscriptomic landscape. The finding was published in Molecular Cell.
The researchers first showed a global A-to-I difference between m6A-positive and m6A-negative RNAs transcribed from the same gene loci. The preferentially presence of A-to-I editing in m6A-negative RNA transcripts suggested a negative correlation of m6A and A-to-I.
Knocking down m6A ‘writers’ or ‘eraser’ resulted in a global alteration of A-to-I editing. Mechanistically, inhibition of m6A modification increases the association of m6A-depleted transcripts with ADAR enzymes for A-to-I editing. This result suggested that the unfavorable ADAR1 binding to m6A-transcripts may account for the negative correlation between m6A and A-to-I.
This study was supported by the grants from Chinese Academy of Sciences, National Natural Science Foundation of China, Ministry of Science and Technology and HHMI International Research Scholar Program.
Figure: Negative regulation of m6A modification on A-to-I RNA editing (Image by Dr. YANG Li’s Group)
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