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Dose-dependency of heterochromatin domains reveals subtelomeric structuration in budding yeast

ABSTRACT: The eukaryotic genome is divided into chromosomal domains of distinct gene activities. Transcriptionally silent chromatin is found in subtelomeric regions leading to telomeric position effect (TPE) in yeast, fly and man. Silent chromatin generally initiates at defined loci and tends to propagate from those sites by self-recruitment mechanisms implying the requirement for processes preventing ectopic spreading of silencing. Barrier elements that can block the spread of silent chromatin have been documented, but their relative efficiency is not known. Here we explore the dose-dependency of silencing factors for the extent of TPE in budding yeast. We characterized genome wide the impact of overexpressing the silencing factors Sir2 and Sir3 on the spreading of Sir3 and its impact on coding and non-coding transcription. We thus reveal that extension of silent domains can reach saturation. Analysis of published data sets enabled to uncover that the extension of Sir3 bound domains stops at zones corresponding to transitions of specific histone marks including H3K79 methylation that is deposited by the conserved enzyme Dot1. Importantly, DOT1 is essential for viability when Sir3 is in excess indicating that this transition actively blocks Sir3 spreading. Our work uncovers previously uncharacterized discrete chromosomal domains associated with specific chromatin features and demonstrates that TPE is efficiently restricted to subtelomeres by the preexisting chromatin landscape.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE104391 | GEO | 2018/10/15

REPOSITORIES: GEO

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Expanding heterochromatin reveals discrete subtelomeric domains delimited by chromatin landscape transitions

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2018-10-08 | GSE106499 | GEO

Histone H3 N-terminus Regulates Higher Order Structure of Yeast Heterochromatin

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Project description:The glycolytic enzyme, pyruvate kinase Pyk1 maintains telomere heterochromatin by phosphorylating histone H3T11 (H3pT11), which promotes SIR (silent information regulator) complex binding at telomeres and prevents autophagy-mediated Sir2 degradation. However, the exact action mechanism of H3pT11 is poorly understood. Here, we identify Dot1-catalyzed H3K79 tri-methylation (H3K79me3) as the downstream effector of H3pT11 and uncover how this histone crosstalk regulates autophagy and telomere silencing. Mechanistically, Pyk1-catalyzed H3pT11 directly reduces the binding of Dot1 to chromatin and inhibits Dot1-catalyzed H3K79me3, which leads to transcriptional repression of autophagy genes and reduced autophagy. Despite the antagonism between H3pT11 and H3K79me3, they synergically promote the binding of SIR complex at telomeres to maintain telomere silencing. Furthermore, we identify Reb1 as a telomere-associated factor that recruits Pyk1-containing SESAME (Serine-responsive SAM-containing Metabolic Enzyme) complex to telomere regions to phosphorylate H3T11 and prevent the invasion of H3K79me3 from euchromatin into heterochromatin to maintain telomere silencing. Together, these results uncover a novel histone crosstalk and provide insights into dynamic regulation of silent heterochromatin and autophagy in response to cell metabolism.

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Project description:The glycolytic enzyme, pyruvate kinase Pyk1 maintains telomere heterochromatin by phosphorylating histone H3T11 (H3pT11), which promotes SIR (silent information regulator) complex binding at telomeres and prevents autophagy-mediated Sir2 degradation. However, the exact action mechanism of H3pT11 is poorly understood. Here, we identify Dot1-catalyzed H3K79 tri-methylation (H3K79me3) as the downstream effector of H3pT11 and uncover how this histone crosstalk regulates autophagy and telomere silencing. Mechanistically, Pyk1-catalyzed H3pT11 directly reduces the binding of Dot1 to chromatin and inhibits Dot1-catalyzed H3K79me3, which leads to transcriptional repression of autophagy genes and reduced autophagy. Despite the antagonism between H3pT11 and H3K79me3, they synergically promote the binding of SIR complex at telomeres to maintain telomere silencing. Furthermore, we identify Reb1 as a telomere-associated factor that recruits Pyk1-containing SESAME (Serine-responsive SAM-containing Metabolic Enzyme) complex to telomere regions to phosphorylate H3T11 and prevent the invasion of H3K79me3 from euchromatin into heterochromatin to maintain telomere silencing. Together, these results uncover a novel histone crosstalk and provide insights into dynamic regulation of silent heterochromatin and autophagy in response to cell metabolism.

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