Dataset Information

Genetic and genomewide analysis of simultaneous mutations in acetylated and methylated lysine residues in histone H3 in Saccharomyces cerevisiae.

ABSTRACT: Acetylated and methylated lysine residues in histone H3 play important roles in regulating yeast gene expression and other cellular processes. Previous studies have suggested that histone H3 acetylated and methylated lysine residues may functionally interact through interdependent pathways to regulate gene transcription. A common genetic test for functional interdependence is to characterize the phenotype of a double mutant. Using this strategy, we tested the genetic interaction between histone H3 mutant alleles that simultaneously eliminate acetylated or methylated lysine residues. Our results indicate that mutation of histone H3 acetylated lysine residues alleviates growth phenotypes exhibited by the H3 methylated lysine mutant. In contrast, histone H3 acetylated and methylated lysine mutants display largely independent effects on yeast gene expression. Intriguingly, these expression changes are preferentially associated with chromosomal regions in which histone H3 lysine residues are hypoacetylated and hypomethylated. Finally, we show that the acetylated and methylated lysine mutants have strikingly different effects on the binding of Sir4 to yeast telomeres, suggesting that histone H3 acetylated lysine residues regulate yeast silencing through a mechanism independent of SIR binding.

SUBMITTER: Jin Y

PROVIDER: S-EPMC2644940 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Genetic and genomewide analysis of simultaneous mutations in acetylated and methylated lysine residues in histone H3 in Saccharomyces cerevisiae.

Jin Yi Y Rodriguez Amy M AM Wyrick John J JJ

Genetics 20081215 2

Acetylated and methylated lysine residues in histone H3 play important roles in regulating yeast gene expression and other cellular processes. Previous studies have suggested that histone H3 acetylated and methylated lysine residues may functionally interact through interdependent pathways to regulate gene transcription. A common genetic test for functional interdependence is to characterize the phenotype of a double mutant. Using this strategy, we tested the genetic interaction between histone ...[more]

PMID: 19087956

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Project description:We have performed a comprehensive analysis of the involvement of histone H3 and H4 residues in the regulation of chronological lifespan in yeast and identify four structural groups in the nucleosome that influence lifespan. We also identify residues where substitution with an epigenetic mimic extends lifespan, providing evidence that a simple epigenetic switch, without possible additional background modifications, causes longevity. Residues where substitution result in the most pronounced lifespan extension are all on the exposed face of the nucleosome, with the exception of H3E50, which is present on the lateral surface, between two DNA gyres. Other residues that have a more modest effect on lifespan extension are concentrated at the extremities of the H3-H4 dimer, suggesting a role in stabilizing the dimer in its nucleosome frame. Residues that reduce lifespan are buried in the histone handshake motif, suggesting that these mutations destabilize the octamer structure. All residues exposed on the nucleosome disk face and that cause lifespan extension are known to interact with Sir3. We find that substitution of H4K16 and H4H18 cause Sir3 to redistribute from telomeres and silent mating loci to secondary positions, often enriched for Rap1, Abf1 or Reb1 binding sites, whereas H3E50 does not. The redistribution of Sir3 in the genome can be reproduced by an equilibrium model based on primary and secondary binding sites with different affinities for Sir3. The redistributed Sir3 cause transcriptional repression at most of the new loci, including of genes where null mutants were previously shown to extend chronological lifespan. The transcriptomic profiles of H4K16 and H4H18 mutant strains are very similar, and compatible with a DNA replication stress response. This is distinct from the transcriptomic profile of H3E50, which matches strong induction of oxidative phosphorylation. We propose that the different groups of residues are involved in binding to heterochromatin proteins, in destabilizing the association of the nucleosome DNA, disrupting binding of the H3-H4 dimer in the nucleosome, or disrupting the structural stability of the octamer, each category impacting on chronological lifespan by a different mechanism.

Dataset Information

Genetic and genomewide analysis of simultaneous mutations in acetylated and methylated lysine residues in histone H3 in Saccharomyces cerevisiae.

Publications

Genetic and genomewide analysis of simultaneous mutations in acetylated and methylated lysine residues in histone H3 in Saccharomyces cerevisiae.

Similar Datasets

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