Coordinating multiple histone modifications by the SAGA and SLIK transcription complexes

Distinct post-translational modifications of the histone protein components of chromatin play specific roles in gene regulation, replication, and DNA repair. My work has focused on understanding the roles of two novel components of the similar, yet distinct yeast SAGA and SLIK coactivator complexes involved in histone post-translational modification and gene regulation. Using a combination of biochemical and genetic approaches, we show that both Ubp8 and Chd1 proteins are stable components of both complexes and have distinct functions. Ubp8 displays histone H2B deubiquitinase activity when associated with the complex and promotes transcription of a SAGA-dependent gene, partially by modulating histone H3-K4 methylation. Our study is one of the first to show that regulated removal of ubiquitin from a histone may have a direct biological outcome. Additionally, a chromodomain of Chd1 associates directly with histone H3-K4 methyl marks and this interaction potentiates the HAT activity of SLIK both in vitro and at a SAGA/SLIK-dependent gene in vivo. This result identifies the first chromodomain that recognizes methylated H3-K4 and possibly identifies a larger subfamily of chromodomain proteins with similar recognition properties. Together, these studies demonstrate unique attributes of the SAGA coactivator complexes in histone acetylation, methylation, and deubiquitination. Our results have a profound implication for the understanding of how a cascade of post-translational histone modifications is regulated to establish an epigenetic environment that is competent for gene expression.