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N6-methyladenosine of chromosome-associated regulatory RNA regulates chromatin state and transcription

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Science  31 Jan 2020:
Vol. 367, Issue 6477, pp. 580-586
DOI: 10.1126/science.aay6018

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A new layer of transcriptional control

N6-methyladenosine (m6A) is the most abundant messenger RNA modification in almost all eukaryotes. Liu et al. now show that m6A is also cotranscriptionally added onto various chromosome-associated regulatory RNAs (carRNAs) in mammalian cells. Disruption of m6A modification of these RNAs increases their abundance and promotes gene transcription by increasing the chromatin accessibility. Thus, m6A serves as a switch to regulate carRNA levels by tuning nearby chromatin state and downstream transcription.

Science, this issue p. 580

Abstract

N6-methyladenosine (m6A) regulates stability and translation of messenger RNA (mRNA) in various biological processes. In this work, we show that knockout of the m6A writer Mettl3 or the nuclear reader Ythdc1 in mouse embryonic stem cells increases chromatin accessibility and activates transcription in an m6A-dependent manner. We found that METTL3 deposits m6A modifications on chromosome-associated regulatory RNAs (carRNAs), including promoter-associated RNAs, enhancer RNAs, and repeat RNAs. YTHDC1 facilitates the decay of a subset of these m6A-modified RNAs, especially elements of the long interspersed element-1 family, through the nuclear exosome targeting–mediated nuclear degradation. Reducing m6A methylation by METTL3 depletion or site-specific m6A demethylation of selected carRNAs elevates the levels of carRNAs and promotes open chromatin state and downstream transcription. Collectively, our results reveal that m6A on carRNAs can globally tune chromatin state and transcription.

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