N6-Methyladenosine co-transcriptionally directs the demethylation of histone H3K9me2

A dynamic epigenome is critical for appropriate gene expression in development and health 1 – 5 . Central to this is the intricate process of transcription 6 – 11 , which integrates cellular signaling with chromatin changes, transcriptional machinery and modifications to messenger RNA, such as N 6 -methyladenosine (m 6 A), which is co-transcriptionally incorporated. The integration of these aspects of the dynamic epigenome, however, is not well understood mechanistically. Here we show that the repressive histone mark H3K9me2 is specifically removed by the induction of m 6 A-modified transcripts. We demonstrate that the methyltransferase METTL3/METTL14 regulates H3K9me2 modification. We observe a genome-wide correlation between m 6 A and occupancy by the H3K9me2 demethylase KDM3B, and we find that the m 6 A reader YTHDC1 physically interacts with and recruits KDM3B to m 6 A-associated chromatin regions, promoting H3K9me2 demethylation and gene expression. This study establishes a direct link between m 6 A and dynamic chromatin modification and provides mechanistic insight into the co-transcriptional interplay between RNA modifications and histone modifications. METTL3-induced deposition of N 6 -methyladenosine (m 6 A) in RNA correlates with removal of H3K9me2 genome wide. The m 6 A reader YTHDC1 recruits the H3K9me2 demethylase KDM3B to chromatin.