Repeat DNA in genome organization and stability

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Eukaryotic genomes contain millions of copies of repetitive elements (RE). Although the euchromatic parts of most genomes are clearly annotated, the repetitive/heterochromatic parts are poorly defined. It is estimated that between 50 and 70% of the human genome is composed of REs. Despite this, we know surprisingly little about the physiological relevance, molecular regulation and the composition of these regions. This primarily reflects the difficulty that REs pose for PCR-based assays, and their poor map-ability in next generation sequencing experiments. Here we first summarize the nature and classification of REs and then examine how this has been used in the recent years to broaden our understanding of mechanisms that keep the repetitive regions of our genomes silent and stable.

Section snippets

Repeat classification

Repetitive elements (RE) are simply defined as sequences that occur multiple times in the genome. This encompasses a huge variety of DNA elements of very diverse structure and origin. REs can be grouped into two broad, but distinct classes. Namely, tandem repeats are small nucleotide stretches repeated in a head to tail orientation, while transposable elements are DNA stretches with the ability to move from one place of the genome to another. Despite their discovery nearly half a decade ago [1]

Tandem repeats

Tandem repeats are short, non-coding sequence stretches that are repeated in a head to tail fashion. They can be categorized according to the size of their building block and total length, forming microsatellite and minisatellite categories. Microsatellites include simple di-nucleotide to penta-nucleotide repeats with a total length of hundreds of basepairs (bp), while minisatellites have a unit length of 30–35 bp with a conserved core sequence of 10–15 bp. The total length of minisatellites

Transposable elements (class I versus class II autonomous versus non-autonomous)

Transposable elements are sometimes referred to as selfish DNA, and these sequences have the ability to change their position in the genome. In contrast to tandem repeats, transposable elements have a defined structure: they are of specific size, are flanked by short repeats and often encode for a unique set of proteins. On the basis of the intermediate form that is used for transposition they are divided into class I, or RNA transposons, which travel by a ‘copy and paste’ mechanism through an

Repeat-linked diseases

An increasing number of diseases have been shown to have links to repetitive sequences. Till date, 22 diseases are correlated with changes in the repeat length, most of which are tandem repeat expansions. These include well-known heritable diseases like Huntington's disease, Friedrich Ataxia and the Fragile X syndrome [11]. A main characteristic of these diseases is that an expansion of the repeat over a crucial threshold (e.g., 200 copies) leads to transcriptional repression of the

Repeats in cancer

Besides effects at specific disease genes, both tandem repeats and transposable elements have a major impact on global genome integrity. Palindromic sequences, such as inverted repeats are found to be enriched at common fragile sites in cancer genomes. These are thought to form secondary structures during replication, leading to fork stalling and the formation of double-strand breaks and unscheduled recombination events [18, 19]. Replication forks also tend to slow down and stall at GC-rich

Importance of heterochromatin at RE

Three epigenetic pathways ensure the silencing of RE: methylation of H3K9, DNA methylation and the germ-line specific PIWI pathway. Several recent findings suggest that the three pathways are interconnected and that the importance of each pathway for silencing is dependent on the developmental stage. In somatic cells, as well as in the cells of the germline, transposable elements are enriched for H3K9me3, and  in plants and vertebrates  for DNA CpG methylation as well. Interestingly, the extent

Silencing of RE in the germline

The threat that RE poses to genomic integrity is particularly crucial in germ cells, as genomic changes in germline cells will be transmitted to the next generation. Moreover gross rearrangements early in meiosis may impair meiotic synapsis. Intriguingly, several transposable elements have evolved to be expressed [29], or transposed, exclusively in germ cells [30]. Cells of the germline are also subject to widespread epigenetic reprogramming during which neither DNA methylation, nor  in the

Silencing of RE in somatic cells

A well-studied example of somatic cells is the embryonic stem cell (ESC). These are cultured cells originating from the inner cell mass (ICM) of the blastocyst stage of mammalian embryos. In this system, the silencing of REs is highly dependent on H3K9 methylation, while DNA methylation becomes essential only after further differentiation [28••]. Importantly, the components of the PIWI pathway are not expressed in ESC nor in other somatic cells. On the other hand, studies in Drosophila and

Future challenges

Recent studies have collectively shown that H3K9me, the PIWI pathway and DNA methylation are interdependent for the silencing and stabilization of transposable elements in organisms containing CpG methylation. Moreover, H3K9me seems to be the link that connects RNA-mediated silencing and DNA methylation. The current data suggests a degree of selectivity, specificity, as well as redundancy among H3K9 specific HMTs. A second major conclusion is that three pathways of RE silencing are

References and recommended reading

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

  • • of special interest

  • •• of outstanding interest

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