RNA stability controlled by m6A methylation contributes to X-to-autosome dosage compensation in mammals

In mammals, X-chromosomal genes are expressed from a single copy since males (XY) possess a single X chromosome, while females (XX) undergo X inactivation. To compensate for this reduction in dosage compared with two active copies of autosomes, it has been proposed that genes from the active X chromosome exhibit dosage compensation. However, the existence and mechanisms of X-to-autosome dosage compensation are still under debate. Here we show that X-chromosomal transcripts have fewer m 6 A modifications and are more stable than their autosomal counterparts. Acute depletion of m 6 A selectively stabilizes autosomal transcripts, resulting in perturbed dosage compensation in mouse embryonic stem cells. We propose that higher stability of X-chromosomal transcripts is directed by lower levels of m 6 A, indicating that mammalian dosage compensation is partly regulated by epitranscriptomic RNA modifications. Here, the authors show that transcripts arising from the X chromosome are less decorated by m 6 A and are more stable than their autosomal counterparts. Consistently, acute depletion of m 6 A preferentially stabilizes autosomal transcripts and thus results in aberrant dosage compensation.