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

• Autores: Muhammad, Abubakar; Sarkadi, Zsuzsa; Mazumder, Agnisrota; Ait Saada, Anissia; van Emden, Thomas; Capella, Matias; Fekete, Gergely; Suma Sreechakram, Vishnu N.; Al Sady, Bassem; Lambert, Sarah A E; Papp, Balázs; Barrales, Ramón Ramos; Braun, Sigurd
• Año de publicación: 2024
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: Heterochromatin; Gene silencing; Genetic screen; Schizosaccharomyces pombe
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Heterochromatin plays a critical role in regulating gene expression and maintaining genome integrity. While structural and enzymatic components have been linked to heterochromatin establishment, a comprehensive view of the underlying pathways at diverse heterochromatin domains remains elusive. Here, we developed a systematic approach to identify factors involved in heterochromatin silencing at pericentromeres, subtelomeres and the silent mating type locus in Schizosaccharomyces 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. However, 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. Moreover, similar phenotypic profiles revealed shared functions for subunits within complexes. We further discovered 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 delayed 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.
Fil: Muhammad, Abubakar. Justus Liebig Universitat Giessen; Alemania
Fil: Sarkadi, Zsuzsa. No especifíca;
Fil: Mazumder, Agnisrota. Justus Liebig Universitat Giessen; Alemania
Fil: Ait Saada, Anissia. Universite Paris-saclay (universite Paris-saclay);
Fil: van Emden, Thomas. No especifíca;
Fil: Capella, Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Agrobiotecnología del Litoral. Universidad Nacional del Litoral. Instituto de Agrobiotecnología del Litoral; Argentina
Fil: Fekete, Gergely. No especifíca;
Fil: Suma Sreechakram, Vishnu N.. No especifíca;
Fil: Al Sady, Bassem. No especifíca;
Fil: Lambert, Sarah A E. Universite Paris-saclay (universite Paris-saclay);
Fil: Papp, Balázs. No especifíca;
Fil: Barrales, Ramón Ramos. No especifíca;
Fil: Braun, Sigurd. No especifíca;