Book of Abstracts: Albany 2009
June 16-20 2009
© Adenine Press (2008)
Bidirectional expression of trinucleotide repeats: Studies of the DM1 and FMR1 loci suggest that trinucleotide repeats are associated with an RNA-mediated heterochromatin modification and insulator function
Instability of trinucleotide repeats is associated with numerous human diseases, yet we have little understanding of the normal role of the repeats in chromatin organization and the alteration of this organization following repeat expansion. Studies of the DM1 locus demonstrated that the CTG repeat is flanked by binding sites for the insulator factor CTCF and that the bidirectional transcripts through the repeat are converted to small RNA fragments and are associated with the local repressive H3K9 methylation and HP1 recruitment that is imbedded within a region of euchromatin-associated H3K4 methylation. Current model for heterochromatin formation at repetitive elements involves the processing of bidirectional RNA transcripts into small RNAs, which then recruit repressive chromatin marks and DNA methylation to the region. Indeed, while at the wild type DM1 locus this RNA-mediated local heterochromatin modification is restricted by CTCF insulators, the expansion of the repeats in congenital DM is accompanied by the loss of chromatin insulation function in the region, spreading of heterochromatin and DNA methylation.
Recent studies indicate that several other trinucleotide repeats in the genome, including the CGG repeat at the FMR1 locus, are bidirectionally transcribed and flanked by CTCF binding sites. These findings suggest a conserved mechanism of RNA-mediated chromatin silencing at these repeats where bidirectional transcripts across the repeats may play a role of a primary trigger for a stable repeat-associated repressive chromatin modification that is normally restricted by flanking chromatin insulators, and may lead to heterochromatin spreading upon repeat expansion and loss of chromatin insulator function in the region.
In this context it is also important to emphasize that bidirectional expression of the expanded repeats, in addition to accumulation of mutant sense transcripts, may result in accumulation of mutant antisense transcripts and in some cases mutant proteins as demonstrated by recent studies of the FMR1 locus. This in turn opens the possibility that relative contribution of the bidirectional expression of the expanded repeats may account for variable phenotypes associated with several repeat-associated genetic disorders.
Fred Hutchinson Cancer Research Center