Eukaryotic gene regulation by targeted chromatin re-modeling at dispersed, middle-repetitive sequence elements

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RNA interference might have evolved to minimize the deleterious impact of transposable elements and viruses on eukaryotic genomes, because mutations in genes within the RNAi pathway cause mobilization of transposons in nematodes and flies. Although the first examples of RNAi involved post-transcriptional gene silencing, recently the pathway has been shown to act at the transcriptional level. It does so by establishing a chromatin configuration on the target DNA that has many of the hallmarks of heterochromatin, thus preventing its transcription. Members of dispersed, repeated sequence families appear to have been utilized by the RNAi machinery to regulate nearby genes in yeast. The unusual genomic distribution of three repeated element families in the chicken, fruit-fly and nematode genomes prompts speculation that some of these repeats have been co-opted to control gene expression, either locally or over extended chromosomal domains.

Introduction

DNA sequence families of moderate reiteration frequency (dozens to thousands of copies) comprise a significant part of the genome of plants and animals. Although some of these families are clustered (e.g. the rRNA and histone genes), most are dispersed throughout the genome. This was first demonstrated by an adaptation of the standard re-association experiment of denatured genomic DNA [1]. In plants, anywhere from 10% (Arabidopsis) to 95% (Allium) of the genome is composed of dispersed repetitive DNA as revealed by direct genome sequencing [2] and standard DNA re-association experiments [3], respectively. Animal genomes, in general, have lower levels of interspersed repetitive DNA, ranging from 12–15% in nematodes and flies 4., 5. to 37–46% in mice and humans 6., 7.. Much of this DNA is mobile; it is composed of transposons and retrotransposon families [8]. The best-known are the long interspersed element (LINE) families, the prototypical one of which is the L1 element of mammals, and the short interspersed elements (SINEs), whose best-studied members are the Alu and B1 families in humans and mice respectively. Whereas the SINEs are described as non-autonomous — that is, they are incapable of directing their own transposition — recent work has demonstrated that Alu can be mobilized in trans by an autonomous LINE-1 element [9].

The contribution of retrotransposable elements to the evolution of higher eukaryotic genomes has been reviewed recently [10]. The present review focuses on the role that several lesser-known interspersed repeat-elements may play in regulating gene activity by influencing the architecture of chromatin. More than three decades ago, a model of eukaryotic gene regulation was proposed in which the short, interspersed members of middle-repetitive sequence families acted in cis to control the expression of sets (i.e. ‘batteries’) of structural genes. These genes are activated in response to particular developmental cues, such as hormones [11]. Unusual genomic distributions of several interspersed repeat families and explicit experimental evidence for the orphaned long terminal repeats (LTRs) of yeast transposons lend support to the broad features of this model.

Section snippets

CR1: a non-LTR retrotransposon conserved throughout vertebrate evolution

First discovered in chickens [12] and later shown to be widely distributed throughout the class Aves [13], members of the chicken repeat 1 (CR1) family have been found in reptiles [14], amphibians [15] and fish [16], suggesting a shared evolutionary history of approximately 400 million years. Its presence in an invertebrate [17], suggests an even more ancient origin. Most of the elements are short, with well conserved 3′-ends but severely truncated 5′-termini. However, consensus sequences have

DINE-1 and MITE elements: dispersed repeats with unusual genomic distributions

A non-random genomic distribution of the members of a middle-repetitive dispersed repeat family could be an indication that the family is evolving under functional constraints. Analysis of cosmids and chromosomal in situ revealed that an atypical repeat, DINE-1 (Drosophila interspersed element), is found preferentially on the fourth chromosome of Drosophila melanogaster, where it is present roughly every 3.5 kb [28]. This is in sharp contrast to the long period interspersion pattern of repeats

Orphan LTRs can act as nucleation sites for the formation of heterochromatin and effect gene silencing in fission yeast

The appearance of double stranded RNA (dsRNA) in cells, either by natural or artificial means, triggers a homology-dependent process known as RNA interference (RNAi) that leads to targeted gene silencing. This can occur post-transcriptionally, either through degradation of the targeted transcript or by interfering with the translation of the targeted mRNA 34.•, 35.•, 36.••. Of more relevance to this review is the involvement of the RNAi pathway in forms of transcriptional gene silencing [37].

Conclusions

The dispersed copies of the CR1, DINE-1 and MITE repeated DNA families are not distributed randomly throughout the chicken, fruit-fly and nematode genomes where they comprise a significant component of the interspersed repetitive DNA. Their unusual localizations suggest that these elements may be evolving under functional constraints. It has been discovered that orphan LTRs of yeast retrotransposons can act as nucleation sites for the establishment of an RNAi-dependent silent chromatin

References and recommended reading

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

  • • of special interest

  • •• of outstanding interest

Acknowledgements

I would like to thank the Felsenfeld laboratory for generously providing the unpublished sequence of the region upstream of the chicken globin insulator. I am indebted to Sandra O’Keefe for assisting with the CR1 searches in this region and for preparing the figures in the manuscript.

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