Trans-histone crosstalk establishes distinct H3K79 methylation zones with differential transcriptional functions.

H3K79 methylation by Dot1 (disruptor of telomeric silencing-1) plays critical roles in multiple cellular processes potentially by modulating chromatin structure and gene expression. However, the genome-wide distribution patterns of H3K79me1, H3K79me2, and H3K79me3 and the mechanisms specifying these patterns remain unclear. Here, we mapped H3K79 methylation patterns across the yeast genome using ChIP-seq and identified three distinct gene groups, termed state-specific methylation zones, each predominantly marked by one methylation state. These zones remain largely stable during transcriptional reprogramming. They may be established and/or maintained via H2B ubiquitination by the Rad6-Bre1 complex: loss of Rad6 leads to the complete loss of the H3K79me3 zone, converting it into an H3K79me1-enriched region while simultaneously diminishing the H3K79me1 zone. Loss of H4K16 acetylation also similarly disrupted the H3K79me1 zone, albeit weakly. Interestingly, Dot1 occupancy does not always correlate with the H3K79me3 level, as translation-related genes exhibit high Dot1 occupancy but are depleted of H3K79me3. Functionally, H3K79me3 and H3K79me1 appear to play differential roles in transcriptional regulation: Dot1-activated genes are enriched for H3K79me3, whereas a majority of Dot1-repressed genes are associated with H3K79me1. We therefore propose that H3K79 methylation states define specific chromatin zones that contribute to differential transcriptional outputs and whose establishment and maintenance depend on trans-histone crosstalk.