Epigenetic gene regulation by noncoding RNAs

doi:10.1016/S0955-0674(03)00041-3

Current Opinion in Cell Biology

Volume 15, Issue 3, June 2003, Pages 281-289

https://doi.org/10.1016/S0955-0674(03)00041-3 Get rights and content

Abstract

Functional noncoding RNAs have distinct roles in epigenetic gene regulation. Large RNAs have been shown to control gene expression from a single locus (Tsix RNA), from chromosomal regions (Air RNA), and from entire chromosomes (roX and Xist RNAs). These RNAs regulate genes in cis; although the Drosophila roX RNAs can also function in trans. The chromatin modifications mediated by these RNAs can increase or decrease gene expression. These results suggest that the primary role of RNA molecules in epigenetic gene regulation is to restrict chromatin modifications to particular regions of the genome. However, given that RNA has been shown to be at the catalytic core of other ribonucleoprotein complexes, it is also possible that RNA also plays a role in modulating changes in chromatin structure.

Introduction

Epigenetic gene regulation refers to heritable changes in gene expression without alteration of the DNA sequence. Functional noncoding RNAs are implicated in regulating several epigenetic phenomena. Many examples of RNA-dependent silencing require gene products that are also necessary for RNA interference (RNAi), including post-transcriptional and transcriptional gene silencing in Arabidopsis and Drosophila, quelling in Neurospora, and silencing of mating type loci and centromeres in Schizosaccharomyces pombe (reviewed in 1., 2., 3., 4.). Mammalian dosage compensation and genomic imprinting provide examples of epigenetic gene regulation in which noncoding RNAs are used to establish monoallelic expression from specific regions of the genome. In flies, an RNA-containing complex directs transcriptional activation, indicating that noncoding RNAs can stimulate transcription as well as silence gene expression.

In this review, we will focus on recent advances in understanding the roles of noncoding RNAs in genomic imprinting and dosage compensation in flies and mammals.

Section snippets

Dosage compensation in fruit flies

In Drosophila, gene expression from the X chromosome is equalized by doubling the transcription rate from the single X chromosome in XY males relative to XX females [5]. In male flies, the male-specific lethal (MSL) complex spreads hyperactive chromatin bidirectionally from 30–40 chromatin entry sites located on the X chromosome (Figure 1a) [6]. The MSL complex contains six proteins: MSL1, a novel acidic protein; MSL2, a Ring-finger protein; MSL3, a chromodomain protein; MLE, an RNA helicase;

Xist RNA regulates dosage compensation in mammals

Dosage compensation in mammals is accomplished by the transcriptional silencing of one X chromosome in XX females, through a process known as X-inactivation (reviewed in [17]). X-inactivation is a random process in primates and the mouse embryo; the maternal or paternal X chromosome has an equal probability of being inactivated in every cell. As in Drosophila, a RNP complex that spreads in cis along the X chromosome appears to accomplish dosage compensation in mammals (Figure 1b). The Xist/XIST

The noncoding RNA Tsix negatively regulates Xist

Tsix is transcribed in the antisense direction through the Xist locus and plays a crucial role in dictating which X chromosome will become the active X (Xa) and the Xi 36., 37., 38.. Tsix loss-of-function mutations have different effects on random and imprinted X-inactivation 37., 38., 39.•, 40.•, 41.•.

In female mouse ES cells, Tsix is expressed from both X chromosomes before and during differentiation, but not after it. Deletion of Tsix cis-regulatory elements or insertion of a polyadenylation

Gene silencing by the noncoding RNA Air

The genes Igf2r, Slc22a2 and Slc22a3 comprise one of a growing group of imprinted gene clusters in which antisense RNAs are implicated in the regulation of monoallelic expression (Table 1). Igf2r, Slc22a2 and Slc22a3 are imprinted genes expressed exclusively from the maternal allele [49]. Air, which exhibits imprinted expression exclusively from the paternal allele, overlaps Igf2r and is transcribed in the antisense direction through this locus (Figure 1, Figure 2). Air does not overlap Slc22a2

Conclusions

Noncoding RNA plays a crucial role in several instances of epigenetic gene regulation. In genomic imprinting and dosage compensation, noncoding RNAs generally act in cis to regulate one allele of a gene pair. Several imprinted clusters encode antisense RNAs, and these antisense transcripts are implicated in regulating changes in chromatin structure over small genetic distances. Antisense transcripts might destabilize and/or inactivate a complementary functional transcript, as suggested for Tsix

Update

Two recent reports reveal that Eed and Enx1 are transiently enriched on the Xi at the onset of X-inactivation 55.••, 56.••. In addition, H3 methylated at Lys27 is enriched on the Xi, and the Eed–Enx1 complex is required to establish this histone modification. Xist expression is both necessary and sufficient for the recruitment of the Eed–Enx1 complex and for the methylation of H3-K27.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

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of special interest
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of outstanding interest

Acknowledgements

The authors would like to thank Hannah Cohen, Cecile de la Cruz, Susanna Mlynarczyk-Evans, Dmitri Nusinow, Kathrin Plath, Morgan Royce-Tolland, Katie Worringer, Richard Collins and David Lum for critical reading of the manuscript. B Panning is funded by Howard Hughes Medical Institute research grant 76296-549901, National Institutes of Health grant GM 63671-01, and a grant from the Sandler Family Supporting Foundation. AA Andersen is supported by a Canadian Institutes of Health Research

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Epigenetic gene regulation by noncoding RNAs

Abstract

Introduction

Section snippets

Dosage compensation in fruit flies

Xist RNA regulates dosage compensation in mammals

The noncoding RNA Tsix negatively regulates Xist

Gene silencing by the noncoding RNA Air

Conclusions

Update

References and recommended reading

Acknowledgements

Curr. Opin. Plant. Biol.

Cell

Curr. Biol.

Curr. Opin. Cell. Biol.

Cell

Mol. Cell

Mol. Cell

Curr. Opin. Gen. Dev.

Mol. Cell

Proc. Natl. Acad. Sci. USA

Mol. Cell Biol.

Genes Dev.

Nat. Genet.

Hum. Mol. Genet.

Am. J. Hum. Genet.

Genes Dev.

Nat. Genet.

Molecular biology. An RNA-guided pathway for the epigenome

Science

JIL-1, a chromosomal kinase implicated in regulation of chromatin structure, associates with the male specific lethal (MSL) dosage compensation complex

J. Cell Biol.

The NTPase/helicase activities of Drosophila maleless, an essential factor in dosage compensation

EMBO J.

Targeting the chromatin-remodeling MSL complex of Drosophila to its sites of action on the X chromosome requires both acetyl transferase and ATPase activities

EMBO J.

The roX genes encode redundant male-specific lethal transcripts required for targeting of the MSL complex

EMBO J.

Extent of chromatin spreading determined by roX RNA recruitment of MSL proteins

Science

Recruitment of the male-specific lethal (MSL) dosage compensation complex to an autosomally integrated roX chromatin entry site correlates with an increased expression of an adjacent reporter gene in male Drosophila

J. Biol. Chem.

Association and spreading of the Drosophila dosage compensation complex from a discrete roX1 chromatin entry site

EMBO J.

Xist RNA and the mechanism of X chromosome inactivation

Annu. Rev. Genet.

Conditional deletion of Xist disrupts histone macroH2A localization but not maintenance of X inactivation [Letter]

Nat. Genet.

Chromosomal silencing and localization are mediated by different domains of Xist RNA

Nat. Genet.