Instability and chromatin structure of expanded trinucleotide repeats

Abstract

Trinucleotide repeat expansion underlies at least 17 neurological diseases. In affected individuals, the expanded locus is characterized by dramatic changes in chromatin structure and in repeat tract length. Interestingly, recent studies show that several chromatin modifiers, including a histone acetyltransferase, a DNA methyltransferase and the chromatin insulator CTCF can modulate repeat instability. Here, we propose that the unusual chromatin structure of expanded repeats directly impacts their instability. We discuss several potential models for how this might occur, including a role for DNA repair-dependent epigenetic reprogramming in increasing repeat instability, and the capacity of epigenetic marks to alter sense and antisense transcription, thereby affecting repeat instability.

Figure 1

Modulators of trinucleotide repeat instability. A number of gene products have been shown to modify trinucleotide repeat instability throughout mouse development^{, -}. Msh2 and Msh3 are required for instability in all stages investigated for CAG/CTG repeats^{, -}. Postmeiotic segregation increased 2 (Pms2) as well as Ogg1 are specifically involved in somatic repeat instability. Dnmt1, on the other hand, protects against expansions in an expanded CAG model only in the germlines . Ataxia telangiectasia and Rad3 related (Atr), a signaling kinase, prevents expansion in the female germline and age-dependent instability in somatic tissues of CGG repeats. It should be noted that Msh6 null mice have mild triplet repeat instability phenotypes in mice, but this observation has been generally dismissed due to its effect on the stability of Msh2 and Msh3 ^{, ,} .

Figure 2

Models for chromatin-dependent trinucleotide repeat instability. Expanded trinucleotide repeats (orange) are embedded into heterochromatin, which is enriched in H3K9me and DNA methylation at CpG sites (blue circles). Here, we present three speculative mechanisms by which chromatin environment might impact repeat instability. We imagine that these models might act in parallel at different loci, tissues, or developmental stages. i) Heterochromatin as a recruitment signal during reprogramming. During germline development and early embryogenesis, DNA is demethylated, probably through a DNA repair mechanism. DNA methylation at CpGs leads to recruitment of DNA repair factors (green circles), creating nicks that eventually lead to repeat instability. ii) Chromatin structure as a cis-acting factor in triplet repeat instability. Loose euchromatin could facilitate the access of DNA repair factors to aberrantly structured repeat tract. Promoting access would enhance gratuitous repair of the repeat tract and therefore instability (open circles are unmethylated CpG sites). iii) Transcription in triplet repeat instability. Sense, antisense, or convergent transcription through an expanded repeat could promote secondary DNA structure formation and therefore instability.