R-loops Associated with Triplet Repeat Expansions Promote Gene Silencing in Friedreich Ataxia and Fragile X Syndrome

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Friedreich ataxia and Fragile X syndrome are among 40 human diseases associated with expansion of repeated sequences. In both disorders repeat expansion leads to gene silencing, the molecular mechanism of which is not well understood, impeding the development of specific therapies to treat these disorders. It is proposed that formation of unusual DNA structures (RNA/DNA hybrids, or R-loops) over repeat regions may play a role, but their molecular function has not been investigated in vivo. We show that R-loops form on expanded repeats of FXN and FMR1 genes in cells from FRDA and FXS patients. These R-loops are stable, correlate with repressive chromatin marks and hinder FXN transcription in patient cells. We studied the relationship between repressive chromatin and R-loops. Decrease in the amount of repressive chromatin has no effect on R-loop levels. In contrast, increase in the R-loops leads to transcriptional silencing of FXN gene and formation of repressive chromatin, providing a direct molecular link between R-loops and pathology of expansion diseases. This discovery is important for understanding the basic molecular mechanism underlying the pathology of expansion diseases. The ability of R-loops to trigger transcriptional silencing makes them an attractive target for future therapeutic approaches to treat these diseases.

Vyšlo v časopise: R-loops Associated with Triplet Repeat Expansions Promote Gene Silencing in Friedreich Ataxia and Fragile X Syndrome. PLoS Genet 10(5): e32767. doi:10.1371/journal.pgen.1004318
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004318

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