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  • Review Article
  • Published:

Epigenetic silencing of RNA polymerase I transcription

Nature Reviews Molecular Cell Biology volume 4, pages 641–649 (2003)Cite this article

Key Points

  • Ribosomal RNA genes can be silenced on a large scale, by the inactivation of entire nucleolus organizer regions (NORs) in genetic hybrids, or on a smaller scale, by silencing individual rRNA genes within an NOR.

  • Techniques that probe the accessibility of rRNA genes in a chromatin environment, including those using the sensitivity to deoxyribonucleases or the DNA crosslinking agent psoralen, have shown that changes in chromatin accessibility correlate with changes in rRNA gene transcription in yeast, plants and mammals.

  • Silenced rRNA genes are derepressed if DNA methylation or histone deacetylation is perturbed, implicating chromatin modifications in rRNA gene silencing.

  • New insight into rRNA gene silencing mechanisms has come from the characterization of NoRC, a SNF2h-containing chromatin remodelling complex that is recruited to mammalian rRNA gene promoters by the DNA-binding factor TTF-I. NoRC interaction with the rRNA gene promoter brings about transcriptional silencing coincident with de novo cytosine methylation, histone deacetylation and histone H3 lysine 9 methylation.

  • Future challenges include the need to understand how rRNA genes are chosen for activation or repression, how NoRC is targeted to establish or maintain silencing, how overall chromatin organization is affected by localized rRNA gene silencing and how epigenetic marks are inherited.

Abstract

The genes that encode ribosomal RNA exist in two distinct types of chromatin — an 'open' conformation that is permissive to transcription and a 'closed' conformation that is transcriptionally refractive. Recent studies have provided insights into the molecular mechanisms that silence either entire nucleolus organizer regions (NORs) in genetic hybrids or individual rRNA genes within a NOR. An emerging theme from these studies is that epigenetic mechanisms operating at the level of DNA methylation and histone modifications alter the chromatin structure and control the ratio of active and inactive rRNA genes.

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Figure 1: Nucleolar dominance.
Figure 2: DNA methylation impairs binding of upstream binding factor (UBF) to nucleosomal rRNA genes.
Figure 3: Active and silent ribosomal genes are demarcated by their associated proteins.
Figure 4: SNF2-containing chromatin-remodelling complexes.
Figure 5: Model of NoRC-mediated rRNA gene silencing.

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Acknowledgements

Our apologies to all colleagues whose work has not been cited in the original because of space constraints. We thank the members of our laboratories and anonymous reviewers for critical comments and discussion. Research in the Grummt lab has been supported by the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie and the BMBF. Research in the Pikaard lab is supported by the National Institutes of Health, the National Science Foundation and the United States Department of Agriculture.

Author information

Authors and Affiliations

  1. Division of Molecular Biology of the Cell II, German Cancer Research Center, Heidelberg, D-69120, Germany

    Ingrid Grummt

  2. Biology Department, Washington University, 1 Brookings Drive, St Louis, 63130, Missouri, USA

    Craig S. Pikaard

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  1. Ingrid Grummt
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Related links

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DATABASES

FlyBase

ISWI

Su(var)3-9

InterPro

AT-hook

bromodomain

PHD

LocusLink

ACF1

CBP

HDACs

p300

TAF1

WSTF

OMIM

α-thalassaemia X-linked mental retardation (ATR-X) syndrome

Saccharomyces Genome Database

Rrn3

Sap30

Swiss-Prot

CARM1

Cockayne's Syndrome B

DNMT1

DNMT3a

DNMT3b

PCAF

Rpd3

Sin3

SUV39H

Swi6

TIF-IA

TIP5

TTF-I

UBF

Glossary

NUCLEOLUS ORGANIZER REGION

(NOR). Cluster of genes, arrayed head-to-tail, that encodes precursor ribosomal RNAs. A NOR includes active rRNA genes, which give rise to secondary constrictions of metaphase chromosomes, and silent rRNA genes, which are compacted in heterochromatin.

RNA POLYMERASE I

(Pol I). One of three classes of eukaryotic nuclear DNA-dependent RNA polymerases that is located in the nucleolus and is responsible for the synthesis of precursor ribosomal RNA (pre-rRNA), which, in vertebrates, is processed into 28S, 5.8S and 18S rRNAs.

EPIGENETIC

Any heritable change in gene expression that is not caused by a change in DNA sequence.

EUCHROMATIN

Chromosome region that does not stain intensely with DNA-binding dyes due to the fact that the chromatin is relatively uncondensed. Transcriptionally active genes are typically located within euchromatic regions of the genome.

HETEROCHROMATIN

A densely staining, highly condensed form of chromatin that generally corresponds to transcriptionally inactive regions of the genome.

PRE-INITIATION COMPLEX

The full set of transcription factors and RNA polymerase subunits correctly assembled on the gene promoter such that transcription can take place if nucleotide triphosphates are provided.

CpG RESIDUE

DNA methylation in mammalian cells occurs at the 5′-position of cytosine within CpG dinucleotides. By convention, the phosphate forming the phosphodiester bond between the cytosine and guanosine residues is included.

HETEROCHROMATIN PROTEIN 1

(HP1). A non-histone chromosomal protein first identified in Drosophila but with homologues in mammals and plants. HP1 is implicated in establishing and maintaining higher-order chromatin structures and in gene silencing.

HISTONE METHYLTRANSFERASE

Enzyme that transfers methyl groups onto lysine or arginine residues of histones. The enzyme typically has a domain known as the SET domain (an acronym formed using the first letters for the three founding members of the family).

CHROMATIN IMMUNOPRECIPITATION

(ChIP). A technique that isolates specific gene sequences from formaldehyde-fixed soluble chromatin using antibodies that recognize specific chromosomal proteins.

HISTONE DEACETYLASE

Enzyme that removes acetyl groups from lysines. Histone deacetylation is typically correlated with transcriptional inactivity.

BROMODOMAIN

A highly conserved sequence motif that is present in many chromatin-associated proteins and recognizes acetylated lysine residues.

PHD FINGER

A zinc-finger-like motif that is involved in protein–protein interactions and chromatin-mediated gene regulation.

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Grummt, I., Pikaard, C. Epigenetic silencing of RNA polymerase I transcription. Nat Rev Mol Cell Biol 4, 641–649 (2003). https://doi.org/10.1038/nrm1171

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