Preprint: RNA m6A modifications recruit DNA methyltransferases to establish heritable gene silencing in human cells

A preprint deposited on bioRxiv describes a mechanistic connection between RNA N6-methyladenosine (m6A) modifications and the establishment of de novo DNA methylation in human cells. The work, from researchers using orthogonal CRISPR platforms, genome-wide CRISPR screens, and proximity-dependent proteomics, reports that the m6A writer complex — which deposits methyl groups onto adenosine residues in RNA — is recruited to chromatin in association with DNA methyltransferases (DNMTs), and that this interaction is required for establishing heritable epigenetic silencing at target loci.

DNA methylation, primarily at CpG dinucleotides, is the most abundant epigenetic modification in the human genome and plays central roles in gene regulation, embryogenesis, cellular differentiation, and disease. How de novo methylation patterns are targeted to specific genomic locations has been an open question, with evidence implicating transcription, non-coding RNAs, and chromatin state. This study proposes m6A-marked RNA as an additional guidance mechanism that bridges the transcriptome and the epigenome.

The genome-wide screen data nominate specific components of the m6A and DNMT machinery as participants in a shared pathway. If the findings hold up to peer review, they would represent a new layer of epigenetic crosstalk relevant to development, ageing, and disease states in which DNA methylation patterns are disrupted — including cancer.

This is a preprint and has not yet undergone peer review. Findings should be interpreted with appropriate caution.