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Genetics, Vol. 179, 277-289, May 2008, Copyright © 2008
doi:10.1534/genetics.107.085068
Regulators of Cellular Levels of Histone Acetylation in Saccharomyces cerevisiae
Weimin Peng*,
Cynthia Togawa*,
Kangling Zhang
and
Siavash K. Kurdistani*,1
* Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California 90095 and Mass Spectrometry Core Facility, Department of Biochemistry, School of Medicine, Loma Linda University, Loma Linda, California 92354
1 Corresponding author: Department of Biological Chemistry, David Geffen School of Medicine, UCLA, 615 Charles Young Dr. S., BSRB Room 377B, P.O. Box 951737, Los Angeles, CA 90095-1737.
E-mail: skurdistani{at}mednet.ucla.edu
Histone acetylation levels are regulated through the opposing activities of histone acetyltransferases (HATs) and deacetylases (HDACs). While much is known about gene-specific control of histone acetylation, little is understood about how total or cellular levels of histone acetylation are regulated. To identify regulators of cellular levels of histone acetylation, we developed an immunofluorescence-based approach to screen the single-gene deletion library of Saccharomyces cerevisiae for strains with significant reductions in cellular histone acetylation levels. Of the 4848 mutants screened, we identified 63 strains with considerable cellular hypoacetylation of N-terminal lysines in histones H3 and H4. The cellular hypoacetylation was validated for subsets of the identified strains through secondary screens including mass spectrometric analysis of individual lysines and chromatin immunoprecipitation of specific genomic loci. Among the identified mutants were several members of the Ccr4-Not complex, V-type ATPases, and vacuolar protein-sorting complexes as well as genes with unknown functions. We show that Gcn5, a major HAT in yeast, has diminished histone acetyltransferase activity in particular mutants, providing a plausible explanation for reduction of cellular acetylation levels in vivo. Our findings have revealed unexpected and novel links between histone acetylation, Gcn5 HAT activity, and diverse processes such as transcription, cellular ion homeostasis, and protein transport.