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Small non-protein coding RNAs are involved in pathways that control the genome at the level of chromatin. In  Schizosaccharomyces pombe , small interfering RNAs (siRNAs) are required for the faithful propagation of heterochromatin that is found at peri-centromeric repeats. In contrast to repetitive DNA, protein-coding genes are refractory to siRNA-mediated heterochromatin formation, unless siRNAs are expressed in mutant cells. Here we report the identification of 20 novel mutant alleles that enable  de novo  formation of heterochromatin at a euchromatic protein-coding gene by using  trans -acting siRNAs as triggers. For example, a single amino acid substitution in the pre-mRNA cleavage factor Yth1 enables siRNAs to trigger silent chromatin formation with unparalleled efficiency. Our results are consistent with a kinetic nascent transcript processing model for the inhibition of small-RNA-directed  de novo  formation of heterochromatin and lay a foundation for further mechanistic dissection of cellular activities that counteract epigenetic gene silencing.

An enhancer screen identifies new suppressors of small-RNA-mediated epigenetic gene silencing