Role of the Ccr4‐Not Complex in Histone Acetylation

Abstract

The Ccr4‐Not complex is a global regulator of gene expression that affects expression both positively and negatively. The complex, conserved from yeast to human, is composed of at least nine subunits. The Ccr4 subunit functions in the control of mRNA deadenylation and transcriptional initiation/elongation. The NOT proteins are involved in transcriptional repression by restricting access of TFIID to promoters. The Ccr4‐Not complex also plays a key role in sensing nutrients and stress. Our earlier results implicated Ccr4‐Not complex in regulation of global untargeted histone acetylation. This notion is also supported by the synthetic negative genetic interactions between the ccr4Δ and not4Δ mutations and mutations in SAGA and NuA4, the main histone acetyltransferases in yeast. The histone hypoacetylation phenotype of ccr4Δ and not4Δ mutants can be partially suppressed by attenuated expression of acetyl‐CoA carboxylase ACC1. This result suggests that ccr4Δ and not4Δ mutants have altered regulation of intermediary metabolism, reduced level of nucleocytosolic acetyl‐CoA, and consequently display histone hypoacetylation. Together, our data highlight the connection between intermediary metabolism and histone acetylation and indicate that the nucleocytosolic level of acetyl‐CoA is an important determinant of histone acetylation.This work was funded by NIH.