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,[1] while heterochromatin formation has been shown to require at least argonaute and an RNA-dependent RNA polymerase.[2] Loss of these genes in S. pombe results in abnormal heterochromatin organization and impairment of centromere function,[3] resulting in lagging chromosomes on anaphase during cell division.[4]

Function and mechanisms

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 using the Chp1 protein 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 to form more RITS complexes.[5] The RITS complex localizes to heterochromatic regions through the base pairing of the nascent heterochromatic transcripts as well as through the Chp chromodomain which recognizes methylated histones found in heterochromatin.[6] Once incorporated into the heterochromatin, the RITS complex is also known to play a role in the recruitment of other RNAi complexes as well as other chromatin modifying enzymes to specific genomic regions.[7] Heterochromatin formation, but possibly not maintenance, is dependent on the ribonuclease protein dicer, which is used to generate the initial complement of siRNAs.[8]

Importance in other species

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.[9] It is known, however, that plants and animals have analogous mechanism for small RNA-guided heterochromatin formation, and it is believed that the mechanisms described above for S. pombe are highly conserved and play some role in heterochromatin formation in mammals as well. In higher eukaryotes, RNAi-dependent heterochromatic silencing appears to play a larger role in germline cells than in primary cells or cell lines, and is only one of the many different forms of gene silencing used throughout the genome, making it more difficult to study.[10]

The role of RNAi in transcriptional gene silencing in plants has been characterized fairly well, and functions primarily through DNA methylation via the RdDM pathway. In this process, which is distinct from the process described above, argonaut-bound siRNA recognizes nascent RNA transcripts or the target DNA to guide the methylation and silencing of the target genomic region.[11]

References
  1. Verdel A, Jia S, Gerber S, Sugiyama T, Gygi S, Grewal S, Moazed D (2004). "RNAi-mediated targeting of heterochromatin by the RITS complex". Science. 303 (5658): 672–6. doi:10.1126/science.1093686. PMC 3244756. PMID 14704433.
  2. Irvine D, Zaratiegui M, Tolia N, Goto D, Chitwood D, Vaughn M, Joshua-Tor L, Martienssen R (2006). "Argonaute slicing is required for heterochromatic silencing and spreading". Science. 313 (5790): 1134–7. doi:10.1126/science.1128813. PMID 16931764.
  3. Volpe T, Kidner C, Hall I, Teng G, Grewal S, Martienssen R (2002). "Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi". Science. 297 (5588): 1833–7. doi:10.1126/science.1074973. PMID 12193640.
  4. Volpe T, Schramke V, Hamilton G, White S, Teng G, Martienssen R, Allshire R (2003). "RNA interference is required for normal centromere function in fission yeast". Chromosome Res. 11 (2): 137–46. doi:10.1023/A:1022815931524. PMID 12733640.
  5. Sugiyama T, Cam H, Verdel A, Moazed D, Grewal S (2005). "RNA-dependent RNA polymerase is an essential component of a self-enforcing loop coupling heterochromatin assembly to siRNA production". Proc Natl Acad Sci USA. 102 (1): 152–7. doi:10.1073/pnas.0407641102. PMC 544066. PMID 15615848.
  6. Volpe, Tom; Martienssen, Robert A. (2011-09-01). "RNA Interference and Heterochromatin Assembly". Cold Spring Harbor Perspectives in Biology. 3 (9): a003731. doi:10.1101/cshperspect.a003731. ISSN 1943-0264. PMC 3181039. PMID 21441597.
  7. Moazed, Danesh (2009-01-22). "Small RNAs in transcriptional gene silencing and genome defence". Nature. 457 (7228): 413–420. doi:10.1038/nature07756. ISSN 0028-0836. PMC 3246369. PMID 19158787.
  8. Noma K, Sugiyama T, Cam H, Verdel A, Zofall M, Jia S, Moazed D, Grewal S (2004). "RITS acts in cis to promote RNA interference-mediated transcriptional and post-transcriptional silencing". Nat Genet. 36 (11): 1174–80. doi:10.1038/ng1452. PMID 15475954.
  9. Wang F, Koyama N, Nishida H, Haraguchi T, Reith W, Tsukamoto T (2006). "The assembly and maintenance of heterochromatin initiated by transgene repeats are independent of the RNA interference pathway in mammalian cells". Mol Cell Biol. 26 (11): 4028–40. doi:10.1128/MCB.02189-05. PMC 1489094. PMID 16705157.
  10. Volpe, Tom; Martienssen, Robert A. (2011-09-01). "RNA Interference and Heterochromatin Assembly". Cold Spring Harbor Perspectives in Biology. 3 (9): a003731. doi:10.1101/cshperspect.a003731. ISSN 1943-0264. PMC 3181039. PMID 21441597.
  11. Matzke, Marjori; Kanno, Tatsuo; Daxinger, Lucia; Huettel, Bruno; Matzke, Antonius J. M. (2009-06-01). "RNA-mediated chromatin-based silencing in plants". Current Opinion in Cell Biology. 21 (3): 367–376. doi:10.1016/j.ceb.2009.01.025. ISSN 1879-0410. PMID 19243928.
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