Posttranslational modifications of histone proteins play important roles in regulating chromatin dynamics and transcription (24
). Most of these modifications are located in the flexible N-terminal tails that protrude from the nucleosome, while some occur in the globular core domains of histones. In either case, nucleosome structure can be altered directly, or indirectly, by modifications and the activities that these modifications recruit.
Histone modifications are dynamic and highly regulated and are under tight control by enzymes that either add or remove them. For example, in Saccharomyces cerevisiae
, histone H2B is monoubiquitylated by Rad6 at lysine 123 (H2BK123ub1) during transcription, and this mark is localized over the coding region of genes (48
). Removal of H2BK123ub is mediated by the deubiquitylases Ubp8 and Ubp10, although Ubp10 functions more at heterochromatic regions (8
). In an ubp8
Δ mutant, which has persistent H2BK123ub1, recruitment of Ctk1 kinase is hindered and the phosphorylation of Ser2 on the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II is altered (69
). Thus, both the timely addition and removal of ubiquitin on K123 are necessary for optimal transcription. In conjunction with the FACT complex (Spt16/Pob3), ubiquitylated H2B facilitates both the removal and reassembly of nucleosomes before and after the passage of RNA polymerase II (RNAPII) during elongation (14
). H2BK123ub1 is clearly linked to chromatin dynamics during elongation, but it is unclear how the ubiquitylation machinery recognizes nucleosomes and if disruption of the canonical nucleosome structure by RNAPII is required for modification of K123.
Histone modifications also regulate one another, providing cross talk among the histones (27
). In “trans
-histone” regulation, the modification on one histone modulates the modification on another histone protein. One of the most well known examples of trans
-histone regulation is the requirement of H2BK123ub1 for H3K4 di- and trimethylation during transcription (10
). In S. cerevisiae
, methylation of H3K4 is catalyzed by COMPASS, which contains the Set1 methyltransferase (9
). H3K4 can be mono-, di-, and trimethylated, and the different methylation states represent different facets of active chromatin. H3K4 trimethylation peaks at the promoter of actively transcribed genes and has been suggested to recruit Isw1 chromatin remodelers and the NuA3 histone acetylation complex, both of which remodel chromatin and facilitate transcription, to genes (18
). H3K4 dimethylation is present in the middle of genes and may serve as a mark of recent transcription, while H3K4 monomethylation rises toward the 3′ end (23
). H2BK123ub1 is required for H3K4 di- and trimethylation by controlling the incorporation of Cps35 into the COMPASS complex (28
). The presence of Cps35 within COMPASS is required to form a highly active complex capable of di- and trimethylating H3K4.
Most histone modifications occur on the N-terminal domain of histones H3 and H4. For this reason, the roles of H3 and H4 tails in regulating nuclear functions have been studied extensively. In contrast, very little is known about the function of the H2A and H2B tails in transcriptional regulation. Interestingly, the limited number of data suggest that the H2A and H2B tails play a more prominent role in repression of transcription (29
). To explore the function of the histone H2A N-terminal domain in transcription, we analyzed modification levels for various histone modifications in the histone H2A tail mutants. Our results revealed that the H2A tail is required for the activation of highly induced genes and that a region previously identified as a H
epression domain, HAR, controls the level of H2BK123 monoubiquitylation and subsequently H3K4 methylation. The close proximity of the HAR to H2BK123 and its partial occlusion by nucleosomal DNA suggest a novel histone cross talk between H2A and H2BK123ub1 that may depend on the exposure of the HAR during transcription-linked nucleosome disruption. The implications of this pathway on the coordination of histone modifications during transcription are discussed.