The specific roles of cohesin-SA1 in telomere cohesion and gene expression: implications for cancer and development

Resumen

The specific roles of cohesin-SA1 for telomere cohesion and gene expression: Implications for cancer and development" Cohesin is a protein complex originally identified for its role in sister chromatid cohesion. Increasing evidence portrays this complex as a major organizer of interphase chromatin. In vertebrate somatic cells, there are two cohesin complexes that consist of Smc1, Smc3, Rad21 and either SA1 or SA2. To explore their functional specificity and their relevance for cancer and development, we generated a mouse model deficient for SA1. Mouse embryos lacking SA1 die before birth and show developmental delay and features reminiscent of Cornelia de Lange Syndrome (CdLS), a genetic disorder linked to cohesin dysfunction. SA1-heterozygous mice have shorter lifespan and earlier onset of tumorigenesis. SA1-deficient cells present decreased proliferation and increased aneuploidy as a result of chromosome segregation defects. These defects are not caused by impaired centromere cohesion, which depends on cohesin-SA2. Instead, we found that they arise from defective telomere replication, which requires cohesion mediated specifically by cohesin-SA1. In addition, analysis of genome-wide cohesin distribution reveals that SA1 is responsible for the accumulation of the complex at promoters and sites bound by the chromatin insulator CTCF. In the absence of SA1, cohesin-SA2 redistributes away from those sites and transcription of several genes is altered. Among them we found genes involved in biological processes related to CdLS pathogenesis. The presence of cohesin-SA1 at gene promoters positively regulates the expression of genes such as Myc or Protocadherins, a function that cannot be compensated by cohesin-SA2. Moreover, the cohesin-binding pattern along gene clusters is altered in the absence of SA1 and affects the transcriptional regulation of the genes within. Thus, cohesin-SA1 prevents generation of aneuploidy and tumorigenesis by assuring an efficient telomere replication, while its impaired function in gene expression regulation most likely underlies the etiology of CdLS.