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RITS—connecting transcription, RNA interference, and heterochromatin assembly in fission yeast

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In recent years, a bevy of evidence has been unearthed indicating that ‘silent’ heterochromatin is not as transcriptionally inert as once thought. In the unicellular yeast Schizosaccharomyces pombe, the processing of transcripts derived from centromeric repeats into homologous short interfering RNA (siRNA) is essential for the formation of centromeric heterochromatin. Deletion of genes required for siRNA biogenesis showed that core components of the canonical RNA interference (RNAi) pathway are essential for centromeric heterochromatin assembly as well as for centromere function. Subsequent purification of the RNA‐induced initiation of transcriptional gene silencing (RITS) complex provided the critical link between siRNAs and heterochromatin assembly, with RITS acting as a physical bridge between noncoding RNA scaffolds and chromatin. Here, we review current understanding of how RITS promotes heterochromatin formation and how it participates in transcription‐coupled silencing. WIREs RNA 2011 2 632–646 DOI: 10.1002/wrna.80

This article is categorized under:

  • RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
  • Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs
  • Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action

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Figure 1.

Sites of heterochromatin assembly in fission yeast. (a) Fission yeast centromeres have a common organization with a central domain consisting of central core (cnt) and inner repeat sequences (imr), which is flanked by the outer repeat elements consisting of dg and dh repeats. Centromere 1 has two copies of dg and dh that symmetrically flank the central domain, and larger centromeres have more copies of the repeats (up to 12 total in centromere 2). (b) At the mating‐type locus, heterochromatin assembles over a 20‐kb region including mat2P and mat3M sequences. Within this domain, cenH is a 4.3‐kb region with >96% homology to dg and dh sequences. Assembly of heterochromatin on cenH is regulated by RNA interference (RNAi). Additional heterochromatin nucleation sequences exist within the mat2P/mat3M locus, including a 2.1‐kb region between cenH and mat3, which includes REIII. Atf1 and Pcr1 factors recruit histone deacetylase and Clr‐C activity to this domain, which serves as a redundant heterochromatin nucleation site with cenH. (c) Sequencing of telomeres in fission yeast is incomplete, but has shown the presence of dg/dh‐like sequences within tlh1 and tlh2 genes located in subtelomeric domains of the left arm of chromosome 1 and right arm of chromosome 2; 1.1 kb of sequence within each gene shows gapped sequences with >75% identity to centromeric sequences.29 At telomeres, heterochromatin assembly can also be specified independently of RNAi by the telomere‐specific factor Taz1.30

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Figure 2.

The RNA cycle of heterochromatin assembly. Nascent centromeric transcripts expressed during S phase of the cell cycle are converted by RNA‐dependent RNA polymerase complex (RDRC) activity to double‐stranded RNA (dsRNA) for cleavage by Dcr1 to form siRNAs. These siRNAs pass through the Argonaute chaperone complex (ARC) prior to loading into RNA‐induced initiation of transcriptional gene silencing (RITS), where Ago1 endonuclease activity cleaves the passenger strand siRNA, allowing Ago1 to target nascent centromeric transcripts for cotranscriptional gene silencing and to target Ago1 (and RITS) to centromeric transcripts to reinstate transcriptional gene silencing via recruitment of Clr‐C (Figure 4).

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Figure 3.

The RNA‐induced initiation of transcriptional gene silencing (RITS) complex. RITS has a linear architecture, with Tas3 bridging between Chp1 and Ago1. Ago1 can bind siRNAs (thick red line) to mediate targeting to and destruction of nascent transcripts (red wavy line), and Chp1 has an N‐terminal chromodomain with high affinity for H3K9me chromatin (red star).

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Figure 4.

The H3K9me cycle. Strains lacking RNA interference (RNAi) machinery retain low levels of H3K9me at centromeres, suggesting some RNAi‐independent Clr‐C recruitment as seen at other sites of heterochromatin. H3K9me can be bound by the histone methyltransferase complex, Clr‐C, allowing ‘spreading’ of the H3K9me mark to adjacent nucleosomes. High‐affinity binding of H3K9me by Chp1 chromodomain promotes efficient recruitment of RNA‐induced initiation of transcriptional gene silencing (RITS)/RNA‐dependent RNA polymerase complex (RDRC), which in turn can recruit Clr‐C and amplify the H3K9me signal through an RNAi‐dependent mechanism. H3K9me then promotes transcriptional gene silencing. The H3K9me and RNA cycles (Figure 2) are tightly linked via RITS to promote efficient heterochromatin assembly.

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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs
Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action

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