RNA m6A mediates de novo DNA methylation and heritable epigenetic silencing in human cells
DNA methylation is the most abundant epigenetic modification on the human genome and changes dynamically during embryogenesis, aging, and disease. How DNA methylation is established de novo remains incompletely understood. Using orthogonal CRISPR platforms to initiate de novo DNA methylation coupled with genome-wide CRISPR screens and proximity-dependent proteomics, we discover the interplay between RNA m6A modifications and de novo DNA methylation to program heritable epigenetic memory in human cells. The RNA m6A writer complex is recruited to chromatin with DNA methyltransferases and histone repressors during the transient establishment phase of heritable epigenetic silencing. Inhibition of RNA m6A during early pluripotent transition leads to defects in de novo DNA methylation, resulting in upregulation of transposable elements that pose a threat to genome integrity during early development. Our work reveals the vital coordination between the epitranscriptome and de novo DNA methylation to establish proper heritable epigenetic silencing in human cells.