RNA-induced transcriptional silencing

RNA-induced transcriptional silencing (RITS) is a form of RNA interference by which short RNA molecules - such as small interfering RNA (siRNA) - trigger the downregulation of transcription of a particular gene or genomic region. This is usually accomplished by posttranslational modification of histone tails (e.g. methylation of lysine 9 of histone H3) which target the genomic region for heterochromatin formation. The protein complex that binds to siRNAs and interacts with the methylated lysine 9 residue of histones H3 is the RITS complex.

RITS was discovered in the fission yeast "Schizosaccharomyces pombe", and has been shown to be involved in the initiation and spreading of heterochromatin in the mating-type region and in centromere formation. The RITS complex in "S. pombe" contains at least a piwi domain-containing RNase H-like argonaute, a chromodomain protein Chp1, and an argonaute interacting protein Tas3 which can also bind to Chp1,cite journal |author=Verdel A, Jia S, Gerber S, Sugiyama T, Gygi S, Grewal S, Moazed D |title=RNAi-mediated targeting of heterochromatin by the RITS complex |journal=Science |volume=303 |issue=5658 |pages=672–6 |year=2004 |pmid=14704433 |doi=10.1126/science.1093686] while heterochromatin formation has been shown to require at least argonaute and an RNA-dependent RNA polymerase.cite journal |author=Irvine D, Zaratiegui M, Tolia N, Goto D, Chitwood D, Vaughn M, Joshua-Tor L, Martienssen R |title=Argonaute slicing is required for heterochromatic silencing and spreading |journal=Science |volume=313 |issue=5790 |pages=1134–7 |year=2006 |pmid=16931764 |doi=10.1126/science.1128813] Loss of these genes in "S. pombe" results in abnormal heterochromatin organization and formation of the chromosome centromeres,cite journal |author=Volpe T, Kidner C, Hall I, Teng G, Grewal S, Martienssen R |title=Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi |journal=Science |volume=297 |issue=5588 |pages=1833–7 |year=2002 |pmid=12193640 |doi=10.1126/science.1074973] resulting in slow or stalled anaphase during cell division.cite journal |author=Volpe T, Schramke V, Hamilton G, White S, Teng G, Martienssen R, Allshire R |title=RNA interference is required for normal centromere function in fission yeast |journal=Chromosome Res |volume=11 |issue=2 |pages=137–46 |year=2003 |pmid=12733640 |doi=10.1023/A:1022815931524]

The maintenance of heterochromatin regions by RITS complexes has been described as a self-reinforcing feedback loop, in which RITS complexes stably bind the methylated histones of a heterochromatin region and induce co-transcriptional degradation of any nascent messenger RNA (mRNA) transcripts, which are then used as RNA-dependent RNA polymerase substrates to replenish the complement of siRNA molecules.cite journal |author=Sugiyama T, Cam H, Verdel A, Moazed D, Grewal S |title=RNA-dependent RNA polymerase is an essential component of a self-enforcing loop coupling heterochromatin assembly to siRNA production |journal=Proc Natl Acad Sci U S A |volume=102 |issue=1 |pages=152–7 |year=2005 |pmid=15615848 |doi=10.1073/pnas.0407641102] Heterochromatin formation, but possibly not maintenance, is dependent on the ribonuclease protein dicer, which is used to generate the initial complement of siRNAs.cite journal |author=Noma K, Sugiyama T, Cam H, Verdel A, Zofall M, Jia S, Moazed D, Grewal S |title=RITS acts in cis to promote RNA interference-mediated transcriptional and post-transcriptional silencing |journal=Nat Genet |volume=36 |issue=11 |pages=1174–80 |year=2004 |pmid=15475954 |doi=10.1038/ng1452]

The relevance of observations from fission yeast mating-type regions and centromeres to mammals is not clear, as some evidence suggests that heterochromatin maintenance in mammalian cells is independent of the components of the RNAi pathway.cite journal |author=Wang F, Koyama N, Nishida H, Haraguchi T, Reith W, Tsukamoto T |title=The assembly and maintenance of heterochromatin initiated by transgene repeats are independent of the RNA interference pathway in mammalian cells |journal=Mol Cell Biol |volume=26 |issue=11 |pages=4028–40 |year=2006 |pmid=16705157 |doi=10.1128/MCB.02189-05]

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