<i>N</i> ⁶-methyladenosine of chromosome-associated regulatory RNA regulates chromatin state and transcription.

Abstract

<i>N</i> ⁶-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 <i>Mettl3</i> or the nuclear reader <i>Ythdc1</i> 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.