Key Points
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The transcriptional activity of a gene is dependent on the local composition and organization of its chromatin environment.
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Chromatin-based silencing of sequence information is based on three sequential steps: a decision-making process that targets specific silencing complexes to DNA sequences to be inactivated; a chromatin-structuring process that results in efficient inhibition of RNA polymerases or other nuclear enzymes that interfere with genetic information; and the epigenetic part, the propagation of the silent chromatin through DNA replication and mitosis to the daughter cells.
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Heterochromatin formation and Polycomb-mediated gene repression are two major gene-silencing mechanisms responsible for the stable transmission of repressed transcription states through cell generations.
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Heterochromatin and the Polycomb system apply similar molecular mechanisms to gene targeting. These mechanisms include: trans-acting DNA-binding proteins, cis-acting DNA elements, non-coding RNAs and proteins that set and recognize specific histone marks.
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Different targeting pathways acting in parallel could ensure proper silencing of important genomic regions and developmental regulators. Alternatively, some pathways could act separately on specific sets of target genes, whereas others could act in a combinatorial way.
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The initiation of PcG silencing, as well as heterochromatin formation, seems to rely on DNA-binding proteins, implying that the specificity is generated by underlying DNA sequences rather than by certain protein features of the chromatin environment.
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Histone methylation marks and cis-acting non-coding RNAs provide multiple binding sites that may increase the local concentration of heterochromatin and PcG complexes in cis. Although both types of interaction are of relatively low affinity, the multitude of binding sites may generate a local high-affinity environment that acts as a molecular cage to dynamically maintain chromatin-regulating protein complexes in place at the target genes.
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HOTAIR, a trans-acting long intergenic non-coding RNA that is involved in the repression of Polycomb target genes at the mammalian HOXD locus, seems to act as a scaffold, organizing the concerted action of Polycomb repressive complex 2 (PRC2) and the histone H3 lysine 4 (H3K4)-specific demethylase LSD1. Similarly, nascent chromatin-associated transcripts serve as assembly platforms for heterochromatin complexes in fission yeast.
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The maintenance of epigenetic signals through the process of replication may be explained by self-reinforcing loops that propagate histone-methylation patterns to the two daughter strands. On the other hand, the reactivation of the RNAi machinery at centromeric repeats in early S phase resembles the re-establishment of heterochromatin and its propagation through the replication process in fission yeast, offering an attractive alternative model.
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PcG-mediated repression may be the default state, whereas Trithorax group proteins such as mammalian mixed lineage leukaemia 1 (MLL1) may act as anti-silencing factors that bookmark genes during mitosis in order to render them rapidly activatable on mitotic exit.
Abstract
Recent transcriptome analyses show that substantial proportions of eukaryotic genomes can be copied into RNAs, many of which do not encode protein sequences. However, cells have developed mechanisms to control and counteract the high transcriptional activity of RNA polymerases in order to achieve cell-specific gene activity or to prevent the expression of deleterious sequences. Here we compare how two silencing modes — the Polycomb system and heterochromatin — are targeted, established and maintained at different chromosomal locations and how DNA-binding proteins and non-coding RNAs connect these epigenetically stable and heritable structures to the sequence information of the DNA.
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Acknowledgements
We thank M. Bühler, S. Nakhuri and R. Sawarkar for their critical reading of the manuscript. We apologize to authors whose studies could not be cited owing to space limitations. Work in the laboratory of R.P. is funded by the EU-NoE 'Epigenome', the Deutsche Forschungsgemeinschaft (DFG) and the Eidgenössische Technische Hochschule (ETH) Zurich.
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Nature Reviews Genetics article series on Modes of transcriptional regulation
Glossary
- Heterochromatin
-
The portion of the genome that stays highly condensed throughout the cell cycle. Compared with euchromatin, it replicates late in S phase and is relatively gene-poor. Molecularly, heterochromatin is characterized by DNA methylation, histone hypoacetylation, methylation of histone H3 at lysine 9 and the presence of heterochromatin protein 1 (HP1).
- Histone
-
A family of small, highly conserved basic proteins, found in the chromatin of all eukaryotic cells. The core histones (H2A, H2B, H3 and H4) associate with DNA to form a nucleosome. The histone proteins are subject to various chemical modifications, including acetylation, methylation and phosphorylation.
- Constitutive heterochromatin
-
A subtype of heterochromatin that is present at the highly repetitive DNA sequences found at the centromeres and telomeres of chromosomes, where it hinders transposable elements from becoming activated and thereby ensures genome stability and integrity.
- Facultative heterochromatin
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A subtype of heterochromatin that is formed in the euchromatic environment, where heterochromatin proteins are used to stably repress the activity of certain target genes.
- Polycomb group
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(PcG). A class of proteins — originally described in Drosophila melanogaster — that maintain the stable and heritable repression of several genes, including the homeotic genes.
- Genomic imprinting
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The epigenetic marking of a gene on the basis of parental origin, which results in monoallelic expression.
- Poised promoter state
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A promoter bound by the transcription-initiating form of RNA polymerase II while the gene is not being actively transcribed. Transcriptionally poised genes are suggested to be rapidly upregulated in, for example, developmental processes.
- Mating type locus
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A well-studied chromosome region that forms a model for epigenetic gene silencing in Saccharomyces cerevisiae and Schizosaccharomyces pombe. The mating type locus controls the sexual identities of both haploid and diploid cells.
- RNAi
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(RNA interference). Cellular mechanism involved in gene silencing and 'protection' against retroviral and transposable element invasion. Regulated by proteins such as Dicer and Argonaute, which are responsible for the production of small interfering RNAs that target messenger RNAs for cleavage and that localize silencing factors to heterochromatic regions.
- Small interfering RNA
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(siRNA). A short, non-coding RNA (~22-nucleotides long) that is processed from longer double-stranded RNA by the RNAi machinery. Such non-coding RNAs confer target specificity to the silencing complexes in which they reside.
- RNA-induced initiation of transcriptional gene silencing complex
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(RITS complex). An RNAi effector complex required for heterochromatin assembly in fission yeast. It targets centromeric transcripts to induce both H3K9 methylation and small interfering RNA amplification.
- Trithorax group
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(TRXG). A class of proteins — originally identified as suppressors for mutations in PcG genes in Drosophila melanogaster — that maintain the stable and heritable active state of several genes, including the homeotic genes.
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Beisel, C., Paro, R. Silencing chromatin: comparing modes and mechanisms. Nat Rev Genet 12, 123–135 (2011). https://doi.org/10.1038/nrg2932
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DOI: https://doi.org/10.1038/nrg2932
