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云南快乐十分奖金:A SIR-independent role for cohesin in subtelomeric silencing and organization
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Cohesin is a conserved chromatin-associated SMC complex crucial for higher-order chromosome architecture. Cohesin mutations in humans are associated with severe developmental defects thought to arise from altered gene expression. We report that cohesin is an important determinant of subtelomeric gene repression in budding yeast. The conserved histone deacetylase Sir2, along with other silencing factors, is required for telomere silencing. However, silencing in extensive subtelomeric regions is SIR-independent, but poorly understood. We found that cohesin deficiency results in preferential derepression of multiple subtelomeric genes and its contribution to silencing is Sir-independent. Interestingly, cohesin mutants are defective in nuclear envelope tethering and compaction of subtelomeric regions. Our findings suggest that cohesin may directly contribute to subtelomeric silencing by altering telomere organization.
Cohesin is a key determinant of chromosome architecture due to its DNA binding and tethering ability. Cohesin binds near centromeres and chromosome arms and also close to telomeres, but its role near telomeres remains elusive. In budding yeast, transcription within 20 kb of telomeres is repressed, in part by the histone-modifying silent information regulator (SIR) complex. However, extensive subtelomeric repressed domains lie outside the SIR-binding region, but the mechanism of silencing in these regions remains poorly understood. Here, we report a role for cohesin in subtelomeric silencing that extends even beyond the zone of SIR binding. Clusters of subtelomeric genes were preferentially derepressed in a cohesin mutant, whereas SIR binding was unaltered. Genetic interactions with known telomere silencing factors indicate that cohesin operates independent of the SIR-mediated pathway for telomeric silencing. Mutant cells exhibited Mpk1-dependent Sir3 hyperphosphorylation that contributes to subtelomeric derepression to a limited extent. Compaction of subtelomeric domains and tethering to the nuclear envelope were impaired in mutant cells. Our findings provide evidence for a unique SIR-independent mechanism of subtelomeric repression mediated by cohesin.
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Author contributions: D.K. and S.L. designed research; D.K. performed research; D.K. contributed new reagents/analytic tools; D.K. and S.L. analyzed data; D.K. and S.L. wrote the paper; and S.L. supervised the work.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE126364 (accession no. GSE126364).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1816582116/-/DCSupplemental.
Published under the PNAS license.