Genomic Characterization Reveals a Simple Histone H4 Acetylation Code

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-04, Vol.102 (15), p.5501-5506
• Main Authors: Dion, Michael F., Altschuler, Steven J., Wu, Lani F., Rando, Oliver J., Groudine, Mark T.
• Format: Article
• Language: English
• Subjects: Acetylation; Biological Sciences; Cells; Chromatin; Chromosomes, Fungal - genetics; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Fungal; Genes; Genetic mutation; Genetic recombination; Genomics; Histones; Histones - chemistry; Histones - genetics; Histones - metabolism; Hypotheses; Lysine - genetics; Lysine - metabolism; Multigene Family - genetics; Mutation - genetics; Oligonucleotide Array Sequence Analysis; Open reading frames; Protein Processing, Post-Translational; Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Transcription, Genetic - genetics; Yeasts
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0500136102

The histone code hypothesis holds that covalent posttranslational modifications of histone tails are interpreted by the cell to yield a rich combinatorial transcriptional output. This hypothesis has been the subject of active debate in the literature. Here, we investigated the combinatorial complexity of the acetylation code at the four lysine residues of the histone H4 tail in budding yeast. We constructed yeast strains carrying all 15 possible combinations of mutations among lysines 5, 8, 12, and 16 to arginine in the histone H4 tail, mimicking positively charged, unacetylated lysine states, and characterized the resulting genome-wide changes in gene expression by using DNA microarrays. Only the lysine 16 mutation had specific transcriptional consequences independent of the mutational state of the other lysines (affecting ≈100 genes). In contrast, for lysines 5, 8, and 12, expression changes were due to nonspecific, cumulative effects seen as increased transcription correlating with an increase in the total number of mutations (affecting ≈1,200 genes). Thus, acetylation of histone H4 is interpreted by two mechanisms: a specific mechanism for lysine 16 and a nonspecific, cumulative mechanism for lysines 5, 8, and 12.