Chromatin is regulated by cross talk among different histone modifications, which can occur between residues within the same tail or different tails in the nucleosome. The latter is referred to as trans-tail regulation, and the best-characterized example of this is the dependence of H3 methylation on H2B ubiquitylation. Here we describe a novel form of trans-tail regulation of histone modifications involving the N-terminal tail of histone H2A. Mutating or deleting residues in the N-terminal tail of H2A reduces H2B ubiquitylation and H3K4 methylation but does not affect the recruitment of the modifying enzymes, Rad6/Bre1 and COMPASS, to genes. The H2A tail is required for the incorporation of Cps35 into COMPASS, and increasing the level of ubiquitylated H2B in H2A tail mutants suppresses the H3K4 methylation defect, suggesting that the H2A tail regulates H2B-H3 cross talk. We mapped the region primarily responsible for this regulation to the H2A repression domain, HAR. The HAR and K123 of H2B are in close proximity to each other on the nucleosome, suggesting that they form a docking site for the ubiquitylation machinery. Interestingly, the HAR is partially occluded by nucleosomal DNA, suggesting that the function of the H2A cross talk pathway is to restrict histone modifications to nucleosomes altered by transcription.