Identification of regulators of global histone acetylation in yeast Saccharomyces cerevisiae

Histone modifications play important roles in essentially all DNA‐based processes such as transcription. Histones are modified through local, gene‐specific recruitment of histone modifiers by transcription factors and genomewide in a sequence‐independent manner. While the mechanism of targeted histone modification is understood, little is known about how global levels of histone acetylation are regulated. To identify potential regulators of global histone acetylation, using an immunofluorescence‐based approach, we have screened a single‐gene‐deletion library of S. cerevisiae (~5000 mutants) for genes whose deletions result in global reduction in acetylation levels. Sixty‐four mutants were identified, a subset of which has been confirmed through secondary screens including mass spectrometry. While some of the identified genes are unknown, others have been implicated previously in diverse cellular processes such as MAPK signaling, mitochondrial function and intracellular transport but, more importantly, have never been linked to histone acetylation. Our findings have revealed unexpected links between nuclear histone acetylation and seemingly disparate cellular processes in both the nucleus and cytoplasm. Since these processes are conserved among most eukaryotes, this study also provides novel targets for drug design and development for epigenetic therapy of diseases such as cancer.