Science 297(5588): 1818-1819 (Sept 2002)
RNAi and Heterochromatin—a Hushed-Up Affair
Robin Allshire

Sometimes it is necessary to silence genes, a process that involves shutting down regions of active chromatin. Genes can be silenced by methylation of lysine 9 in histone H3 of chromatin, but RNAi also turns out to be important in chromatin-based gene silencing. In a Perspective, Robin Allshire discusses new work (Volpe et al.) that shows how RNAi is able to shut down chromatin in fission yeast by promoting H3 lysine 9 methylation, perhaps by altering the recruitment of enzymes that methylate DNA and histones.

The highly repetitive DNA (heterochromatin) of eukaryotic genomes contains a large number of repeats and transposons. Regions of heterochromatin are frequently associated with centromeres, which are crucial for the segregation of chromosomes during cell division. Transgenes inserted into heterochromatin domains can be shut down through the influence of silent chromatin in this region. The formation of silent chromatin requires that histone H3 of chromatin be deacetylated and then methylated on lysine 9. The methylated lysine 9 residue binds to heterochromatin protein 1 (Swi6 in fission yeast), leading to a block in transcription. Subsequent methylation of the DNA in this region then locks the chromatin into the silent state (1). Genes can also be silenced at the RNA level by RNA interference (RNAi), which depends on the accidental or deliberate expression of double-stranded RNAs (dsRNAs). These dsRNAs are processed and amplified into small interfering RNAs (siNAs) that bind to and degrade any mRNA transcripts with the same sequence, resulting in loss of expression of the genes encoding these mRNAs (2). Although seemingly separate mechanisms, H3 lysine 9 methylation and RNAi were recently found to be part of the same gene-silencing pathway in the fission yeast Schizosaccharomyces pombe. This unexpected discovery is providing new insights into how different forms of chromatin silencing may be triggered.