Control of alternative splicing through siRNA-mediated transcriptional gene silencing
Abstract
When targeting promoter regions, small interfering RNAs (siRNAs) trigger a previously proposed pathway known as transcriptional gene silencing by promoting heterochromatin formation. Here we show that siRNAs targeting intronic or exonic sequences close to an alternative exon regulate the splicing of that exon. The effect occurred in hepatoma and HeLa cells with siRNA antisense strands designed to enter the silencing pathway, suggesting hybridization with nascent pre-mRNA. Unexpectedly, in HeLa cells the sense strands were also effective, suggesting that an endogenous antisense transcript, detectable in HeLa but not in hepatoma cells, acts as a target. The effect depends on Argonaute-1 and is counterbalanced by factors favoring chromatin opening or transcriptional elongation. The increase in heterochromatin marks (dimethylation at Lys9 and trimethylation at Lys27 of histone H3) at the target site, the need for the heterochromatin-associated protein HP1alpha and the reduction in RNA polymerase II processivity suggest a mechanism involving the kinetic coupling of transcription and alternative splicing.
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HP1α recruitment to local H3K9me2 enrichment induced by siRNA targeting correlates with a change in the ratio of distal versus proximal pre-mRNA levels suggesting a decreased local RNA Pol II speed.
“Similarly, HP1α recruitment to local H3K9me2 enrichment induced by siRNA targeting correlates with a change in the ratio of distal versus proximal pre‐mRNA levels suggesting a decreased local RNA Pol II speed (Alló et al, 2009).”
From RNA polymerase II speed: a key player in controlling and adapting transcriptome composition (2021) · cites this paper as Alló et al, 2009
Cites
Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Noncoding RNAs
Rinn, J. L., Kertesz, M., Wang, J. K., Squazzo, S. L., Xu, X. H., Brugmann, S. A., Goodnough, L. H., Helms, J. A., Farnham, P., Segal, E., et al. (2007) · Cell · doi:10.1016/j.cell.2007.05.022 · Cited by 4,246 · see citing works
Biogenesis of small RNAs in animals
Kim, V. N., Han, J., & Siomi, M. C. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2632 · Cited by 3,181 · see citing works
RNA Maps Reveal New RNA Classes and a Possible Function for Pervasive Transcription
Kapranov, P., Cheng, J., Dike, S., Nix, D. A., Duttagupta, R., Willingham, A. T., Stadler, P. F., Jana Hertel, A., Jörg Hackermüller, A., Hofacker, I. L., et al. (2007) · Science · doi:10.1126/science.1138341 · Cited by 2,519 · see citing works
Asymmetry in the Assembly of the RNAi Enzyme Complex
Schwarz, D. S., Hutvágner, G., Du, T., Xu, Z., Aronin, N., & Zamore, P. D. (2003) · Cell · doi:10.1016/s0092-8674(03)00759-1 · Cited by 2,323 · see citing works
Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs
Meister, G., Landthaler, M., Patkaniowska, A., Dorsett, Y., Teng, G., & Tuschl, T. (2004) · Molecular Cell · doi:10.1016/j.molcel.2004.07.007 · Cited by 1,718 · see citing works
MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation
Tay, Y., Zhang, J., Thomson, A. M., Lim, B., & Rigoutsos, I. (2008) · Nature · doi:10.1038/nature07299 · Cited by 1,385 · see citing works
Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes
Watanabe, T., Totoki, Y., Toyoda, A., Kaneda, M., Kuramochi‐Miyagawa, S., Obata, Y., Chiba, H., Kohara, Y., Kono, T., Nakano, T., et al. (2008) · Nature · doi:10.1038/nature06908 · Cited by 1,115 · see citing works
Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes
Tam, O. H., Aravin, A. A., Stein, P., Girard, A., Murchison, E. P., Cheloufi, S., Hodges, E. C., Anger, M., Sachidanandam, R., Schultz, R. M., et al. (2008) · Nature · doi:10.1038/nature06904 · Cited by 1,042 · see citing works
Kuramochi‐Miyagawa, S., Watanabe, T., Gotoh, K., Totoki, Y., Toyoda, A., Ikawa, M., Asada, N., Kojima, K., Yamaguchi, Y., Ijiri, T. W., et al. (2008) · Genes & Development · doi:10.1101/gad.1640708 · Cited by 926 · see citing works
Small Interfering RNA-Induced Transcriptional Gene Silencing in Human Cells
Morris, K. V., Chan, S. W.-L., Jacobsen, S. E., & Looney, D. J. (2004) · Science · doi:10.1126/science.1101372 · Cited by 925 · see citing works
Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy
Kim, D.-H., Behlke, M. A., Rose, S. D., Chang, M.-S., Choi, S., & Rossi, J. J. (2004) · Nature Biotechnology · doi:10.1038/nbt1051 · Cited by 884 · see citing works
Reversal of H3K9me2 by a Small-Molecule Inhibitor for the G9a Histone Methyltransferase
Kubicek, S., O'Sullivan, R. J., August, E. M., Hickey, E. R., Zhang, Q., Teodoro, M. L., Rea, S., Mechtler, K., Kowalski, J. A., Homon, C. A., et al. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.01.017 · Cited by 859 · see citing works
Small RNAs in transcriptional gene silencing and genome defence
Moazed, D. (2009) · Nature · doi:10.1038/nature07756 · Cited by 825 · see citing works
Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA
Yu, W., Gius, D. R., Onyango, P. O., Muldoon‐Jacobs, K., Karp, J. E., Feinberg, A. P., & Cui, H. (2008) · Nature · doi:10.1038/nature06468 · Cited by 801 · see citing works
MicroRNA-directed transcriptional gene silencing in mammalian cells
Kim, D. H., Sætrom, P., Snøve, O., & Rossi, J. J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808830105 · Cited by 705 · see citing works
A Slow RNA Polymerase II Affects Alternative Splicing In Vivo
de la Mata, M., Alonso, C. R., Kadener, S., Fededa, J. P., Blaustein, M., Pelisch, F., Cramer, P., Bentley, D., & Kornblihtt, A. R. (2003) · Molecular Cell · doi:10.1016/j.molcel.2003.08.001 · Cited by 683 · see citing works
Self-citationTufarelli, C., Stanley, J. A. S., Garrick, D., Sharpe, J. A., Ayyub, H., Wood, W. G., & Higgs, D. R. (2003) · Nature Genetics · doi:10.1038/ng1157 · Cited by 547 · see citing works
Persengiev, S. P., Zhu, X., & Green, M. R. (2003) · RNA · doi:10.1261/rna5160904 · Cited by 531 · see citing works
The human SWI/SNF subunit Brm is a regulator of alternative splicing
Batsché, E., Yaniv, M., & Muchardt, C. (2006) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1030 · Cited by 471 · see citing works
Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells
Lorincz, M. C., Dickerson, D. R., Schmitt, M., & Groudine, M. T. (2004) · Nature Structural & Molecular Biology · doi:10.1038/nsmb840 · Cited by 460 · see citing works
Argonaute-1 directs siRNA-mediated transcriptional gene silencing in human cells
Kim, D. H., Villeneuve, L. M., Morris, K. V., & Rossi, J. J. (2006) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1142 · Cited by 407 · see citing works
Yang, N., & Kazazian, H. H. (2006) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1141 · Cited by 398 · see citing works
Endogenous small interfering RNAs in animals
Okamura, K., & Lai, E. C. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2479 · Cited by 364 · see citing works
Morris, K. V., Santoso, S., Turner, A. W., Pastori, C., & Hawkins, P. G. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000258 · Cited by 330 · see citing works
Involvement of AGO1 and AGO2 in mammalian transcriptional silencing
Janowski, B. A., Huffman, K. E., Schwartz, J. C., Ram, R. R., Nordsell, R., Shames, D. S., Minna, J. D., & Corey, D. R. (2006) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1140 · Cited by 327 · see citing works
Coupling of Transcription with Alternative Splicing
Cramer, P., Cáceres, J. F., Cazalla, D., Kadener, S., Muro, A. F., Baralle, F. E., & Kornblihtt, A. R. (1999) · Molecular Cell · doi:10.1016/s1097-2765(00)80372-x · Cited by 310 · see citing works
Self-citationWeinberg, M. S., Villeneuve, L. M., EHSANI, A., Amarzguioui, M., Aagaard, L., CHEN, Z.-X., Riggs, A. D., Rossi, J. J., & Morris, K. V. (2005) · RNA · doi:10.1261/rna.2235106 · Cited by 277 · see citing works
Promoter-associated RNA is required for RNA-directed transcriptional gene silencing in human cells
Jiang, H., Kim, D. H., & Morris, K. V. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701635104 · Cited by 275 · see citing works
Antisense transcripts are targets for activating small RNAs
Schwartz, J. C., Younger, S. T., Nguyen, N.-B., Hardy, D. B., Monia, B. P., Corey, D. R., & Janowski, B. A. (2008) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1444 · Cited by 274 · see citing works
Schor, I. E., Rascovan, N., Pelisch, F., Alló, M., & Kornblihtt, A. R. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810666106 · Cited by 270 · see citing works
Self-citationThree Functional Classes of Transcriptional Activation Domains
Blau, J., Xiao, H., McCracken, S. A., O’Hare, P., Greenblatt, J., & Bentley, D. L. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.5.2044 · Cited by 268 · see citing works
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de la Mata, M., & Kornblihtt, A. R. (2006) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1155 · Cited by 208 · see citing works
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Nogués, G., Kadener, S., Cramer, P., Bentley, D. L., & Kornblihtt, A. R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208418200 · Cited by 189 · see citing works
Self-citationChromatin, transcript elongation and alternative splicing
Kornblihtt, A. R. (2006) · Nature Structural & Molecular Biology · doi:10.1038/nsmb0106-5 · Cited by 173 · see citing works
Self-citationKadener, S., Cramer, P., Nogués, G., et al. (2001) · The EMBO Journal · doi:10.1093/emboj/20.20.5759 · Cited by 150 · see citing works
Multiple Alternative Splicing Markers for Ovarian Cancer
Klinck, R., Bramard, A., Inkel, L., Dufresne‐Martin, G., Gervais-Bird, J., Madden, R., Paquet, É. R., Koh, C., Venables, J. P., Prinos, P., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-2580 · Cited by 147 · see citing works
Self-citationMechanistic principles of chromatin remodeling guided by siRNAs and miRNAs
González, S., Pisano, D. G., & Serrano, M. (2008) · Cell Cycle · doi:10.4161/cc.7.16.6541 · Cited by 136 · see citing works
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Suzuki, K., Juelich, T., Lim, H., Ishida, T., Watanebe, T., Cooper, D. A., Rao, S., & Kelleher, A. D. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m709651200 · Cited by 108 · see citing works
Site-Specific Analysis of Histone Methylation and Acetylation
Umlauf, D., Goto, Y., & Feil, R. (2004) · Humana Press eBooks · doi:10.1385/1-59259-828-5:099 · Cited by 95 · see citing works
Effect of 27nt Small RNA on Endothelial Nitric-Oxide Synthase Expression
Zhang, M., Zhang, C., Shen, Y. H., et al. (2008) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-11-1186 · Cited by 91 · see citing works
Dicer-Dependent Turnover of Intergenic Transcripts from the Human β-Globin Gene Cluster
Haussecker, D., & Proudfoot, N. J. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.21.9724-9733.2005 · Cited by 71 · see citing works
Transcriptional Scaffolds for Heterochromatin Assembly
Cam, H. P., Chen, E. S., & Grewal, S. I. S. (2009) · Cell · doi:10.1016/j.cell.2009.02.004 · Cited by 66 · see citing works
Zhang, M., Zhang, C., Shen, Y. H., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801933200 · Cited by 61 · see citing works
Small interfering RNA induced transcriptional gene silencing in human cells
Morris, K. V. (2007) · The biomedical & life sciences collection. · doi:10.69645/vhcz2546 · Cited by 43 · see citing works
Yokoyama, R. W., Pannuti, A., Ling, H., et al. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00397-07 · Cited by 20 · see citing works
DNA Methylation-Related Chromatin Modification in the Regulation of Mouse δ-Opioid Receptor Gene
Wang, G., Liu, T., Wei, L., et al. (2005) · Molecular Pharmacology · doi:10.1124/mol.105.011056 · Cited by 19 · see citing works
Topological Analysis of Plasmid Chromatin from Yeast and Mammalian Cells
Tong, W. S., Kulaeva, O. I., Clark, D. J., et al. (2006) · Journal of Molecular Biology · doi:10.1016/j.jmb.2006.07.015 · Cited by 13 · see citing works
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- Authors
- Alló, M., Buggiano, V., Fededa, J. P., Petrillo, E., Schor, I., de la Mata, M., Agirre, E., Plass, M., Eyras, E., Elela, S. A., Klinck, R., Chabot, B., & Kornblihtt, A. R.
- Affiliations
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Université de Sherbrooke (CA)
- Corresponding author
- Kornblihtt, Alberto R
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Published
- 2009-06-21
- Volume
- 16
- Issue
- 7
- Pages
- 717-724
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- OpenAlex
- W1992332038
- Cited by
- 340
- References
- 47
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 8 · 2023: 15 · 2022: 17 · 2021: 12 · 2020: 11 · 2019: 18 · 2018: 8 · 2017: 21 · 2016: 21 · 2015: 34 · 2014: 31 · 2013: 37 · 2012: 30
- FWCI
- 12.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- ANU Open Research (Australian National University) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- alternative splicing, siRNA, transcriptional silencing, heterochromatin, AGO1, HP1α, histone H3 lysine methylation, RNA polymerase II processivity, hepatoma cells, HeLa cells
- MeSH terms
- Chromobox Protein Homolog 5, Animals, Base Sequence, Exons, Fibronectins, HeLa Cells, Carcinoma, Hepatocellular, Heterochromatin, Histones, Humans, Liver Neoplasms, Lysine, Male, Methylation, Promoter Regions, Genetic, RNA Polymerase II, Transcription, Genetic, Oligonucleotides, Antisense, Alternative Splicing, RNA Interference, RNA, Small Interfering, Eukaryotic Initiation Factors, Ribonuclease III, Epigenesis, Genetic, Mice, Gene Knockdown Techniques, Argonaute Proteins
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