Article Dans Une Revue Nucleic Acids Research Année : 2024

A systematic quantitative approach comprehensively defines domain-specific functional pathways linked to Schizosaccharomyces pombe heterochromatin regulation

Abubakar Muhammad
Zsuzsa Sarkadi
Agnisrota Mazumder
Anissia Ait Saada
Thomas van Emden
Matias Capella
Gergely Fekete
Vishnu N Suma Sreechakram
Bassem Al-Sady
Sarah a E Lambert
Balázs Papp
Ramón Ramos Barrales
Sigurd Braun

Résumé

Heterochromatin pla y s a critical role in regulating gene e xpression and maint aining genome integrit y. While str uct ural and enzymatic components ha v e been link ed to heterochromatin establishment, a comprehensiv e vie w of the underlying pathw a y s at div erse heterochromatin domains remains elusiv e. Here, w e de v eloped a systematic approach to identify factors involved in heterochromatin silencing at pericentromeres, subtelomeres and the silent mating type locus in Sc hizosacc haromyces pombe . Using quantitative measures, iterative genetic screening and domain-specific heterochromatin reporters, we identified 369 mutants with different degrees of reduced or enhanced silencing. As expected, mutations in the core heterochromatin machinery globally decreased silencing. Ho w e v er, most other mutants exhibited distinct qualitative and quantitative profiles that indicate heterochromatin domain-specific functions, as seen for example for metabolic pathways affecting primarily subtelomere silencing. Moreo v er, similar phenotypic profiles re v ealed shared functions for subunits within comple x es. We further disco v ered that the uncharacterized protein Dhm2 plays a crucial role in heterochromatin maintenance, affecting the inheritance of H3K9 methylation and the clonal propagation of the repressed state. Additionally, Dhm2 loss resulted in dela y ed S-phase progression and replication stress. Collectively, our systematic approach unveiled a landscape of domain-specific heterochromatin regulators controlling distinct states and identified Dhm2 as a previously unknown factor linked to heterochromatin inheritance and replication fidelity.

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hal-04889922 , version 1 (15-01-2025)

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Abubakar Muhammad, Zsuzsa Sarkadi, Agnisrota Mazumder, Anissia Ait Saada, Thomas van Emden, et al.. A systematic quantitative approach comprehensively defines domain-specific functional pathways linked to Schizosaccharomyces pombe heterochromatin regulation. Nucleic Acids Research, 2024, 52, pp.13665 - 13689. ⟨10.1093/nar/gkae1024⟩. ⟨hal-04889922⟩
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