H3K4me3 instructs transcription at intergenic active regulatory elements [ATAC-seq]

Tri-methylation of lysine 4 on histone H3 (H3K4me3) is a deeply conserved and functionally important histone modification enriched at transcriptionally active promoters. H3K4me3 can facilitate RNA polymerase activity in a context-dependent manner. Here, we generated an epigenetic editing tool, dCas9-PRDM9, that efficiently deposits H3K4me3 at specific target loci, and used it to interrogate the genomic and chromatin contexts required for H3K4me3 to facilitate transcription in human cells. We found that H3K4me3 deposition is sufficient to increase transcription at active candidate cis-regulatory elements (cCREs), and that this effect was independent of cCRE identity or distance from gene promoters, unrelated to transcript levels of putative target genes, and dependent on the presence of active chromatin features. We conclude that H3K4me3 is sufficient to instruct RNA polymerase activity but requires pre-existing features of transcriptionally active chromatin. These findings suggest that disease-associated dysfunction in H3K4me3 deposition or removal can disrupt the cell’s transcriptional state.