Reactome: A Curated Pathway Database

Transcriptional regulation by small RNAs

Stable Identifier
Homo sapiens
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Recent evidence indicates that small RNAs participate in transcriptional regulation in addition to post-transcriptional silencing. Components of the RNAi machinery (ARGONAUTE1 (AGO1, EIF2C1), AGO2 (EIF2C2), AGO3 (EIF2C3), AGO4 (EIF2C4), TNRC6A, and DICER) are observed associated with microRNAs (miRNAs) in both the cytosol and the nucleus (Robb et al. 2005, Weinmann et al. 2009, Doyle et al. 2013, Nishi et al. 2013, Gagnon et al. 2014). The AGO:miRNA complexes are imported into the nucleus by IMPORTIN-8 (IPO8, IMP8, RANBP8) and also by an unknown importin while associated with the nuclear shuttling protein TNRC6A (reviewed in Schraivogel and Meister 2014).
Within the nucleus, AGO2, TNRC6A, and DICER may associate in a complex (Gagnon et al. 2014). Nuclear AGO1 and AGO2 in complexes with small RNAs are observed to activate transcription (RNA activation, RNAa) or repress transcription (Transcriptional Gene Silencing, TGS) of genes that contain sequences matching the small RNAs (reviewed in Malecova and Morris 2010, Huang and Li 2012, Gagnon and Corey 2012, Huang and Li 2014, Salmanidis et al. 2014, Stroynowska-Czerwinska et al. 2014). TGS is associated with methylation of cytosine in DNA and methylation of histone H3 at lysine-9 and lysine-27 (Castanotto et al. 2005, Suzuki et al. 2005, Kim et al. 2006, Weinberg et al. 2006, Kim et al. 2008, reviewed in Malecova and Morris 2010, Li et al. 2014); RNAa is associated with methylation of histone H3 at lysine-4 (Huang et al. 2012, reviewed in Li et al. 2014). Small RNAs in the nucleus have also been shown to play roles in alternative splicing (Liu et al., 2012, Ameyar-Zazoua et al., 2012) and DNA damage repair (Wei et al., 2012; Francia et al., 2012). Nevertheless, elucidation of the detailed mechanisms of small RNA action requires further research.

Literature References
PubMed ID Title Journal Year
22053081 Upregulation of Cyclin B1 by miRNA and its implications in cancer Nucleic Acids Res. 2012
19771207 Prolonged transcriptional silencing and CpG methylation induced by siRNAs targeted to the HIV-1 promoter region J RNAi Gene Silencing 2005
20373265 Transcriptional gene silencing through epigenetic changes mediated by non-coding RNAs Curr. Opin. Mol. Ther. 2010
21948593 Expanding the action of duplex RNAs into the nucleus: redirecting alternative splicing Nucleic Acids Res. 2012
23882114 The double-stranded RNA binding domain of human Dicer functions as a nuclear localization signal RNA 2013
22283730 Argonaute and the nuclear RNAs: new pathways for RNA-mediated control of gene expression Nucleic Acid Ther 2012
24680896 Direct transcriptional regulation by nuclear microRNAs Int. J. Biochem. Cell Biol. 2014
24388755 RNAi factors are present and active in human cell nuclei Cell Rep 2014
24468964 The panorama of miRNA-mediated mechanisms in mammalian cells Cell. Mol. Life Sci. 2014
25131816 Import routes and nuclear functions of Argonaute and other small RNA-silencing proteins Trends Biochem. Sci. 2014
22336708 miRNA goes nuclear RNA Biol 2012
15963934 Short hairpin RNA-directed cytosine (CpG) methylation of the RASSF1A gene promoter in HeLa cells Mol. Ther. 2005
22445173 A role for small RNAs in DNA double-strand break repair Cell 2012
16373483 The antisense strand of small interfering RNAs directs histone methylation and transcriptional gene silencing in human cells RNA 2006
15643423 Specific and potent RNAi in the nucleus of human cells Nat. Struct. Mol. Biol. 2005
23150874 Human TNRC6A is an Argonaute-navigator protein for microRNA-mediated gene silencing in the nucleus RNA 2013
22722852 Site-specific DICER and DROSHA RNA products control the DNA-damage response Nature 2012
22961379 Argonaute proteins couple chromatin silencing to alternative splicing Nat. Struct. Mol. Biol. 2012
18852463 MicroRNA-directed transcriptional gene silencing in mammalian cells Proc. Natl. Acad. Sci. U.S.A. 2008
16936726 Argonaute-1 directs siRNA-mediated transcriptional gene silencing in human cells Nat Struct Mol Biol 2006
24384674 Demystifying the nuclear function of Argonaute proteins RNA Biol 2014
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