Abstract
Soon after its discovery 75 years ago, heterochromatin, a dense chromosomal material, was found to silence genes. But its importance in regulating gene expression was controversial. Long thought to be inert, heterochromatin is now known to give rise to small RNAs, which, by means of RNA interference, direct the modification of proteins and DNA in heterochromatic repeats and transposable elements. Heterochromatin has thus emerged as a key factor in epigenetic regulation of gene expression, chromosome behaviour and evolution.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Heitz, E. Das heterochromatin der Moose. Jehrb. Wiss. Botanik 69, 762–818 (1928).
Hennig, W. Heterochromatin. Chromosoma 108, 1–9 (1999).
Muller, H. J. Types of visible variations induced by X-rays in Drosophila. J. Genetics 22, 299–334 (1930).
Comfort, N. C. From controlling elements to transposons: Barbara McClintock and the Nobel Prize. Trends Genet. 17, 475–478 (2001).
Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).
Lachner, M. & Jenuwein, T. The many faces of histone lysine methylation. Curr. Opin. Cell Biol. 14, 286–298 (2002).
Brehm, A., Tufteland, K. R., Aasland, R. & Becker, P. B. The many colours of chromodomains. Bioessays 26, 133–140 (2004).
Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nature Genet. 33 (Suppl.), 245–254 (2003).
Tamaru, H. & Selker, E. U. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414, 277–283 (2001).
Lindroth, A. M. et al. Requirement of CHROMOMETHYLASE3 for maintenance of CpXpG methylation. Science 292, 2077–2080 (2001).
Bartee, L., Malagnac, F. & Bender, J. Arabidopsis cmt3 chromomethylase mutations block non-CG methylation and silencing of an endogenous gene. Genes Dev. 15, 1753–1758 (2001).
Jackson, J. P., Lindroth, A. M., Cao, X. & Jacobsen, S. Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature 416, 556–560 (2002).
Malagnac, F., Bartee, L. & Bender, J. An Arabidopsis SET domain protein required for maintenance but not establishment of DNA methylation. EMBO J. 21, 6842–6852 (2002).
Tariq, M. et al. Erasure of CpG methylation in Arabidopsis alters patterns of histone H3 methylation in heterochromatin. Proc. Natl Acad. Sci. USA 100, 8823–8827 (2003).
Lippman, Z., May, B., Yordan, C., Singer, T. & Martienssen, R. Distinct mechanisms determine transposon inheritance and methylation via small interfering RNA and histone modification. PLoS Biol. 1, E67 (2003).
Johnson, L., Cao, X. & Jacobsen, S. Interplay between two epigenetic marks. DNA methylation and histone H3 lysine 9 methylation. Curr. Biol. 12, 1360–1367 (2002).
Fuks, F., Hurd, P. J., Deplus, R. & Kouzarides, T. The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res. 31, 2305–2312 (2003).
Fuks, F. et al. The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J Biol. Chem. 278, 4035–4040 (2003).
Lehnertz, B. et al. Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr. Biol. 13, 1192–1200 (2003).
Nguyen, C. T. et al. Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2′-deoxycytidine. Cancer Res. 62, 6456–6461 (2002).
Jeddeloh, J. A., Stokes, T. L. & Richards, E. J. Maintenance of genomic methylation requires a SWI2/SNF2-like protein. Nature Genet. 22, 94–97 (1999).
Gendrel, A. V., Lippman, Z., Yordan, C., Colot, V. & Martienssen, R. A. Dependence of heterochromatic histone H3 methylation patterns on the Arabidopsis gene DDM1. Science 297, 1871–1873 (2002).
Vongs, A., Kakutani, T., Martienssen, R. A. & Richards, E. J. Arabidopsis thaliana DNA methylation mutants. Science 260, 1926–1928 (1993).
Kankel, M. W. et al. Arabidopsis MET1 cytosine methyltransferase mutants. Genetics 163, 1109–1122 (2003).
Martienssen, R. A. & Colot, V. DNA methylation and epigenetic inheritance in plants and filamentous fungi. Science 293, 1070–1074 (2001).
Lippman, Z. L. et al. Role of transposable elements in heterochromatin and epigenetic control. Nature 430, 471–476 (2004).
Kato, M., Miura, A., Bender, J., Jacobsen, S. E. & Kakutani, T. Role of CG and non-CG methylation in immobilization of transposons in Arabidopsis. Curr. Biol. 13, 421–426 (2003).
Matzke, M. et al. Genetic analysis of RNA-mediated transcriptional gene silencing. Biochim. Biophys. Acta 1677, 129–141 (2004).
Grewal, S. I. Transcriptional silencing in fission yeast. J. Cell Physiol. 184, 311–318 (2000).
Volpe, T. A. et al. Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science 297, 1833–1837 (2002).
Reinhart, B. J. & Bartel, D. P. Small RNAs correspond to centromere heterochromatic repeats. Science 297, 1831 (2002).
Bernard, P. et al. Requirement of heterochromatin for cohesion at centromeres. Science 294, 2539–2542 (2001).
Volpe, T. et al. RNA interference is required for normal centromere function in fission yeast. Chromosome Res. 11, 137–146 (2003).
Hall, I. M., Noma, K. & Grewal, S. I. RNA interference machinery regulates chromosome dynamics during mitosis and meiosis in fission yeast. Proc. Natl Acad. Sci. USA 100, 193–198 (2003).
Verdel, A. et al. RNAi-mediated targeting of heterochromatin by the RITS complex. Science 303, 672–676 (2004).
Martienssen, R. A. Maintenance of heterochromatin by RNA interference of tandem repeats. Nature Genet. 35, 213–214 (2003).
Jacobs, S. A. & Khorasanizadeh, S. Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail. Science 295, 2080–2083 (2002).
Schramke, V. & Allshire, R. Hairpin RNAs and retrotransposon LTRs affect RNAi and chromatin-based gene silencing. Science 301, 1069–1074 (2003).
Hall, I. M. et al. Establishment and maintenance of a heterochromatin domain. Science 297, 2232–2237 (2002).
Jia, S., Noma, K. & Grewal, S. I. RNAi-independent heterochromatin nucleation by the stress-activated ATF/CREB family proteins. Science 304, 1971–1976 (2004).
Dernburg, A. F., Zalevsky, J., Colaiacovo, M. P. & Villeneuve, A. M. Transgene-mediated cosuppression in the C. elegans germ line. Genes Dev. 14, 1578–1583 (2000).
Wu-Scharf, D., Jeong, B., Zhang, C. & Cerutti, H. Transgene and transposon silencing in Chlamydomonas reinhardtii by a DEAH-box RNA helicase. Science 290, 1159–1162 (2000).
Aravin, A. A. et al. Double-stranded RNA-mediated silencing of genomic tandem repeats and transposable elements in the D. melanogaster germline. Curr. Biol. 11, 1017–1027 (2001).
Aravin, A. A. et al. The small RNA profile during Drosophila melanogaster development. Dev. Cell 5, 337–350 (2003).
Djikeng, A., Shi, H., Tschudi, C. & Ullu, E. RNA interference in Trypanosoma brucei: cloning of small interfering RNAs provides evidence for retrotransposon-derived 24-26-nucleotide RNAs. RNA 7, 1522–1530 (2001).
Mochizuki, K., Fine, N., Fujisawa, T. & Gorovsky, M. Analysis of a piwi-related gene implicates small RNAs in genome rearrangement in Tetrahymena. Cell 110, 689 (2002).
Taverna, S. D., Coyne, R. S. & Allis, C. D. Methylation of histone H3 at lysine 9 targets programmed DNA elimination in Tetrahymena. Cell 110, 701–711 (2002).
Xie, Z. et al. Genetic and functional diversification of small RNA pathways in plants. PLoS Biol. 2, E104 (2004).
Sijen, T. & Plasterk, R. H. Transposon silencing in the Caenorhabditis elegans germ line by natural RNAi. Nature 426, 310–314 (2003).
Zilberman, D., Cao, X. & Jacobsen, S. E. ARGONAUTE4 control of locus-specific siRNA accumulation and DNA and histone methylation. Science 299, 716–719 (2003).
Lynn, K. et al. The PINHEAD/ZWILLE gene acts pleiotropically in Arabidopsis development and has overlapping functions with the ARGONAUTE1 gene. Development 126, 469–481 (1999).
Soppe, W. J. et al. The late flowering phenotype of fwa mutants is caused by gain-of-function epigenetic alleles of a homeodomain gene. Mol. Cell 6, 791–802 (2000).
Kinoshita, T. et al. One-way control of FWA imprinting in Arabidopsis endosperm by DNA methylation. Science 303, 521–523 (2004).
Chan, S. W. et al. RNA silencing genes control de novo DNA methylation. Science 303, 1336 (2004).
Cao, X. & Jacobsen, S. E. Role of the Arabidopsis DRM methyltransferases in de novo DNA methylation and gene silencing. Curr. Biol. 12, 1138–1144 (2002).
Cao, X. et al. Role of the DRM and CMT3 methyltransferases in RNA-directed DNA methylation. Curr. Biol. 13, 2212–2217 (2003).
Bender, J. & Fink, G. R. Epigenetic control of an endogenous gene family is revealed by a novel blue fluorescent mutant of Arabidopsis. Cell 83, 725–734 (1995).
Mette, M. F., Aufsatz, W., van der Winden, J., Matzke, M. A. & Matzke, A. J. Transcriptional silencing and promoter methylation triggered by double-stranded RNA. EMBO J. 19, 5194–5201 (2000).
Melquist, S. & Bender, J. Transcription from an upstream promoter controls methylation signaling from an inverted repeat of endogenous genes in Arabidopsis. Genes Dev. 17, 2036–2047 (2003).
Zilberman, D. et al. Role of Arabidopsis ARGONAUTE4 in RNA-directed DNA methylation triggered by inverted repeats. Curr. Biol. 14, 1214–1220 (2004).
Fagard, M., Boutet, S., Morel, J. B., Bellini, C. & Vaucheret, H. AGO1, QDE-2, and RDE-1 are related proteins required for post-transcriptional gene silencing in plants, quelling in fungi, and RNA interference in animals. Proc. Natl Acad. Sci. USA 97, 11650–11654 (2000).
Pal-Bhadra, M. et al. Heterochromatic silencing and HP1 localization in Drosophila are dependent on the RNAi machinery. Science 303, 669–672 (2004).
Pal-Bhadra, M., Bhadra, U. & Birchler, J. A. RNAi related mechanisms affect both transcriptional and posttranscriptional transgene silencing in Drosophila. Mol. Cell 9, 315–327 (2002).
Lee, Y. S. et al. Distinct roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA silencing pathways. Cell 117, 69–81 (2004).
Kelly, W. G. et al. X-chromosome silencing in the germline of C. elegans. Development 129, 479–492 (2002).
Maison, C. et al. Higher-order structure in pericentric heterochromatin involves a distinct pattern of histone modification and an RNA component. Nature Genet. 30, 329–334 (2002).
Bernstein, E. et al. Dicer is essential for mouse development. Nature Genet. 35, 215–217 (2003).
Rudert, F., Bronner, S., Garnier, J. M. & Dolle, P. Transcripts from opposite strands of gamma satellite DNA are differentially expressed during mouse development. Mamm. Genome 6, 76–83 (1995).
Deng, W. & Lin, H. miwi a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis. Dev. Cell 2, 819–830 (2002).
Kuramochi-Miyagawa, S. et al. Mili a mammalian member of piwi family gene, is essential for spermatogenesis. Development 131, 839–849 (2004).
Kelley, R. L. & Kuroda, M. I. Noncoding RNA genes in dosage compensation and imprinting. Cell 103, 9–12 (2000).
Reik, W. & Walter, J. Genomic imprinting: parental influence on the genome. Nature Rev. Genet. 2, 21–32 (2001).
Kiyosue, T. et al. Control of fertilization-independent endosperm development by the MEDEA polycomb gene in Arabidopsis. Proc. Natl Acad. Sci. USA 96, 4186–4191 (1999).
Baroux, C., Spillane, C. & Grossniklaus, U. Genomic imprinting during seed development. Adv. Genet. 46, 165–214 (2002).
Sleutels, F. & Barlow, D. P. The origins of genomic imprinting in mammals. Adv. Genet. 46, 119–163 (2002).
Seitz, H. et al. Imprinted microRNA genes transcribed antisense to a reciprocally imprinted retrotransposon-like gene. Nature Genet. 34, 261–262 (2003).
Stam, M., Belele, C., Dorweiler, J. E. & Chandler, V. L. Differential chromatin structure within a tandem array 100 kb upstream of the maize b1 locus is associated with paramutation. Genes Dev. 16, 1906–1918 (2002).
Avner, P. & Heard, E. X-chromosome inactivation: counting, choice and initiation. Nature Rev. Genet. 2, 59–67 (2001).
Heard, E. et al. Methylation of histone H3 at Lys-9 is an early mark on the X chromosome during X inactivation. Cell 107, 727–738 (2001).
Akhtar, A., Zink, D. & Becker, P. B. Chromodomains are protein-RNA interaction modules. Nature 407, 405–409 (2000).
Merok, J. R., Lansita, J. A., Tunstead, J. R. & Sherley, J. L. Cosegregation of chromosomes containing immortal DNA strands in cells that cycle with asymmetric stem cell kinetics. Cancer Res. 62, 6791–6795 (2002).
McClintock, B. Chromosome organization and genic expression. Cold Spring Harbor Symp. Quant. Biol. 16, 13–47 (1951).
McClintock, B., Kato Y., T. A. & Blumenschein, A. Chromosome Constitutions of Races of Maize. Their Significance for Interpreting Relationships Among Races and Strains in the Americas (A monograph.) (Colegio de Postgraduados, Escuela National de Agricultura, Chapingo, Edo. Mexico, 1981).
Fransz, P., Soppe, W. & Schubert, I. Heterochromatin in interphase nuclei of Arabidopsis thaliana. Chromosome Res. 11, 227–240 (2003).
Osborn, T. C. et al. Understanding mechanisms of novel gene expression in polyploids. Trends Genet. 19, 141–147 (2003).
Heath, E. M. & Simmons, M. J. Genetic and molecular analysis of repression in the P-M system of hybrid dysgenesis in Drosophila melanogaster. Genet. Res. 57, 213–226 (1991).
Sarot, E., Payen-Groschene, G., Bucheton, A. & Pelisson, A. Evidence for a piwi-dependent RNA silencing of the gypsy endogenous retrovirus by the Drosophila melanogaster flamenco gene. Genetics 166, 1313–1321 (2004).
Sun, X., Le, H. D., Wahlstrom, J. M. & Karpen, G. H. Sequence analysis of a functional Drosophila centromere. Genome Res. 13, 182–194 (2003).
Arabidopsis Genome Initiative. Analysis of the genome sequence of the flowering plant Arabidopsis thaliana. Nature 408, 796–815 (2000).
Choo, K. H. Domain organization at the centromere and neocentromere. Dev. Cell 1, 165–177 (2001).
Ananiev, E. V., Phillips, R. L. & Rines, H. W. Complex structure of knobs and centromeric regions in maize chromosomes. Tsitol. Genet. 34, 11–15 (2000).
Nagaki, K. et al. Sequencing of a rice centromere uncovers active genes. Nature Genet. 36, 138–145 (2004).
Selker, E. U. et al. The methylated component of the Neurospora crassa genome. Nature 422, 893–897 (2003).
Jorgensen, R. A. in RNAi: A Guide to Gene Silencing (ed. Hannon, G. J.) Ch. 1, 5–21 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 2003).
Kouzminova, E. & Selker, E. U. dim-2 encodes a DNA methyltransferase responsible for all known cytosine methylation in Neurospora. EMBO J. 20, 4309–4323 (2001).
Xiao, W. et al. Imprinting of the MEA Polycomb gene is controlled by antagonism between MET1 methyltransferase and DME glycosylase. Dev. Cell 5, 891–901 (2003).
Colot, V., Maloisel, L. & Rossignol, J. L. Interchromosomal transfer of epigenetic states in Ascobolus: transfer of DNA methylation is mechanistically related to homologous recombination. Cell 86, 855–864 (1996).
Shiu, P. K. & Metzenberg, R. L. Meiotic silencing by unpaired DNA: properties, regulation and suppression. Genetics 161, 1483–1495 (2002).
Freitag, M. et al. DNA methylation is independent of RNA interference in Neurospora. Science 304, 1939 (2004).
Wassenegger, M., Heimes, S., Riedel, L. & Sanger, H. L. RNA-directed de novo methylation of genomic sequences in plants. Cell 76, 567–576 (1994).
Acknowledgements
We thank our collaborators V. Colot and A.-V. Gendrel, and members of our laboratory for discussions. We thank J. Birchler and S. Elgin for permission to reproduce Fig. 1, and A. Frary for comments on the manuscript. Z.L. is the recipient of an Arnold and Mabel Beckman Graduate Student Fellowship of the Watson School of Biological Sciences. R.M is supported by an NSF Plant Genome Program grant and an NIH grant.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Lippman, Z., Martienssen, R. The role of RNA interference in heterochromatic silencing. Nature 431, 364–370 (2004). https://doi.org/10.1038/nature02875
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature02875
This article is cited by
-
Canalization of genome-wide transcriptional activity in Arabidopsis thaliana accessions by MET1-dependent CG methylation
Genome Biology (2022)
-
SMRI: A New Method for siRNA Design for COVID-19 Therapy
Journal of Computer Science and Technology (2022)
-
Increased rates of gene-editing events using a simplified RNAi configuration designed to reduce gene silencing
Plant Cell Reports (2022)
-
Contrasting epigenetic control of transgenes and endogenous genes promotes post-transcriptional transgene silencing in Arabidopsis
Nature Communications (2021)
-
Emerging roles of centromeric RNAs in centromere formation and function
Genes & Genomics (2021)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.
