R-loop biology in health and disease
Our research focuses on understanding the mechanisms governing gene regulation in humans in health and disease conditions. In particular, we are interested in unusual RNA/DNA structures, called R-loops. These are three-stranded structures formed during transcription and composed of an RNA hybridising to a complementary DNA strand, forming an RNA/DNA hybrid, and a displaced single-stranded DNA. R-loops are formed in all living organisms where they play crucial roles in regulating gene expression, DNA and histone modifications, generation of antibody diversity, DNA replication and genome stability. However, dysregulation of R-loops can have severe cellular consequences, since R-loops are associated with pathology of several human diseases, including cancer and neurodegeneration.
We are investigating the molecular basis of neurodegenerative diseases, associated with pathological R-loops. We study Friedreich ataxia and Fragile X syndrome, two of forty human diseases 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. We discovered that R-loops are formed in Friedreich ataxia and Fragile X disorders and promote formation of repressive chromatin on the expanded alleles, leading to FXN and FMR1 transcriptional repression.
In the laboratory, we want to understand the mechanisms underlying regulation of physiological and pathological R-loops in human cells using genome-wide and gene-specific molecular, biochemical and cell biology approaches. The results generated in this project will help us to uncover the molecular mechanisms underlying R-loop functions in healthy human cells and also provide a better understanding of the pathology of R-loop-associated human diseases. In the long term, these findings are essential for the development of new therapeutic approaches for cancer and neurodegenerative disorders.
Scientists interested in our work are welcome to contact Natalia Gromak (email@example.com) for more details.
Nat Genet 52(1):48-55
Cell Rep 23(6):1891-1905
Nat Commun 11;7:13087
PLoS Genetics 10: e1004318
Molecular Cell 42: 794-805
*joint communicating authors