PLoS Genetics 10: e1004630.
Molecular mechanisms of neurodegenerative diseases
Our research focuses on understanding the mechanisms governing gene regulation in humans in health and disease conditions. We are investigating the molecular basis of neurodegenerative diseases arising from dysregulation of RNA transcription and processing. We study Friedreich ataxia (FRDA) and Fragile X syndrome (FXS), two of forty human diseases associated with expansion of small nucleotide sequences.
It is currently not known how the (GAA)n expansion in frataxin (FXN) gene and the (CGG)n expansion in FMR1 gene leads to their transcriptional repression, resulting in human diseases. Recently we discovered that expanded repeats in FXN and FMR1 genes form unusual DNA structures, called R-loops, in patient cells. These are three-stranded structures composed of RNA hybridising to a complementary DNA strand, forming an RNA/DNA hybrid, and a displaced single-stranded DNA. R-loops have been detected in various organisms from bacteria to mammals where they play crucial roles in regulating gene expression, DNA and histone modifications, immunoglobulin class switch recombination, replication and genome stability. We showed that R-loops play a crucial role in human disease. In particular, R-loops are important for the formation of repressive chromatin on the expanded alleles, leading to FXN and FMR1 transcriptional repression.
In the laboratory, we aim to understand the mechanism of heterochromatin formation triggered by R-loops by using various gene-specific and whole-genome molecular and cell biology approaches. The results generated in this project will help us to uncover the molecular mechanisms underlying the pathology of FRDA and FXS and also provide a better understanding of R-loop functions in healthy human cells. In the long term, the findings are essential for the development of new therapeutic approaches for expansion disorders.
PLoS Genetics 10: e1004318.
Molecular Cell 42: 794-805.
*joint communicating authors
Science 325: 90-3.
*joint first authorship