Histone H2B deubiquitylation and transcriptional control in the yeast Saccharomyces cerevisiae
Eukaryotic DNA is condensed into a structure referred to as chromatin. The basic unit of chromatin is the nucleosome, which consists of 146 base pairs of DNA wrapped around an octamer of histone proteins. Histone proteins are highly conserved, as are many of the covalent modifications that alter their function. Known histone modifications include acetylation, phosphorylation, methylation, and ubiquitylation, which have been implicated in a variety of genomic processes including DNA replication, repair, recombination, and transcription. The most extensively studied histone modification to date is lysine acetylation. Histone acetylation is believed to have a positive role in transcription, whereas removal of the acetyl group represses transcription. These observations have led to a model in which genes are regulated by the addition and removal of different histone modifications that act as "on/off" switches for the expression of genes. Histone modifications occur in patterns, and there are instances known in which one modification is required for subsequent modification of another residue. Recently, it was reported that monoubiquitylation of histone H2B on Lysine-123 is required for activation-associated methylation on histone H3 at Lysine-4 and Lysine-79. While the connection to H3 methylation suggests a role for H2B ubiquitylation in activation, there is no direct evidence for the function of this modification in the regulation of gene expression. Here we provide evidence that monoubiquitylation of H2B and subsequent deubiquitylation are both involved in transcriptional activation. H2B deubiquitylation is mediated by the ubiquitin-specific protease, Ubp8, which is a component of the SAGA co-activator complex. Perturbation of the dynamic ubiquitylation/deubiquitylation cycle results in altered levels of H3 methylation at Lysine-4 and Lysine-36, which we partially attribute to defective recruitment of downstream factors to the gene. We propose that H2B ubiquitylation serves, in part, as a "barrier" to transcription factor recruitment during gene induction, and that subsequent deubiquitylation by Ubp8 removes this barrier at the appropriate point in the activation pathway. Finally, we provide evidence that this specific function for Ubp8 occurs within the context of an elongation-specific SAGA-related complex.
Wyce, Anastasia, "Histone H2B deubiquitylation and transcriptional control in the yeast Saccharomyces cerevisiae" (2007). Dissertations available from ProQuest. AAI3271834.