GSE111800
Small RNA-mediated genomic silencing promotes telomere stability in the absence of telomerase
Telomerase deficiency and progressive telomere erosion in human somatic cells results in senescence. Small RNAs that target telomeres have been observed in diverse organisms but their functions are not well characterized. We define an endogenous small RNA pathway in Caenorhabditis elegans that promotes heterochromatin formation at telomeres via Dicer, the perinuclear Argonaute protein WAGO-1 and the nuclear Argonaute protein HRDE-1. Loss of telomerase induces biogenesis of siRNAs that target the telomeric lncRNA TERRA, whereas loss of both telomerase and small RNA-mediated telomeric silencing induces TERRA expression, DNA damage, and an accelerated sterility phenotype. The latter phenotypes can be rescued by exogenous telomeric siRNAs or by loss of the DNA damage response protein EXO-1.  Thus, endogenous siRNAs interact with TERRA to promote heterochromatin formation in a manner that is critical for the stability of naturally eroding telomeres.  We propose that small RNA-mediated heterochromatin defects could contribute to proliferative aging by promoting genome stability. Overall design: RNA-seq of small RNAs from wild-type, trt-1 and trt-1 dcr-1 mixed stage whole worms. Two replicates per genotype.