H3K4me3 methyltransferase KMT2F promotes pre-initiation complex formation by RNA Polymerase I to regulate ribosomal RNA transcription.

Trimethylation of histone 3 lysine 4 (H3K4me3) is mark of active transcription and its regulatory role in RNA polymerase II-mediated transcription has been well-studied. However, if and how this mark regulates RNA polymerase I (RNA Pol I) is not known. Here we used customized genome assemblies for rDNA to demonstrate that KMT2A and KMT2F bind to entire rDNA loci. The binding of these enzymes were mirrored by the binding of H3K4me2 and H3K4me3 marks. Using biochemical assays, we demonstrate the interaction of KMT2- specific subunits with RNA Pol I transcriptional machinery. Our findings reveal KMT2F as the primary KMT depositing the H3K4me3 on rDNA. Loss of H3K4me3 adversely affects the epigenetic landscape and promotes heterochromatization of rDNA locus. Mechanistically, we show that KMT2F promotes pre-initiation complex formation of RNA Pol I. Our findings highlights the thus far undiscovered role of H3K4me3 in the transcriptional initiation of rDNA genes.