Linking mutations in the chromatin remodeller ATRX to inflammation

Rare diseases are classified as those affecting <1 in 2,000 people. Collectively, they affect 1 in 17 people born in the UK.

The Tillotson laboratory studies a class of rare monogenic disorders caused by mutations in genes encoding chromatin factors. Chromatin factors write/read/erase epigenetic marks or remodel chromatin structure to regulate chromatin state and control transcription. The so-called “chromatinopathies” affect multiple tissues, always including the brain. Currently the Tillotson group is focused on a chromatinopathy called ATR-X syndrome, due to hypomorphic mutations in the X-linked gene ATRX. 

The Crow group studies rare monogenic disorders associated with inappropriate stimulation, or defective negative regulation of the type I interferon system. Recently, Crow’s team have discovered patients with ATR-X syndrome who also demonstrate type I interferon induced autoinflammation. 

We are looking for a PhD student to investigate the mechanism underlying this newly discovered and unexpected link between ATRX dysfunction and innate immune system engagement. The project will use cellular and mouse models as well as patient-derived material, and involve experimental techniques such as CRISPR/Cas9 editing, transcriptomics (RNA-sequencing and qPCR), analysis of chromatin binding patterns, co-immunoprecipitation, western blotting and fluorescence microscopy and well as bioinformatic analysis.

https://www.rarediseaseday.org/

Bukowska-Olech, E., Majchrzak-Celińska, A., Przyborska, M., & Jamsheer, A. (2024). Chromatinopathies: insight in clinical aspects and underlying epigenetic changes. In Journal of Applied Genetics (Vol. 65, Issue 2, pp. 287–301). Springer Science and Business Media Deutschland GmbH. https://doi.org/10.1007/s13353-023-00824-1

Crow YJ, Stetson DB. The type I interferonopathies: 10 years on. Nat Rev Immunol. 2022 Aug;22(8):471-483. 

Stevenson, R. E. (2020). Alpha-Thalassemia X-Linked Intellectual Disability Syndrome. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020.

Tillotson, R., Yan, K., Ruston, J., DeYoung, T., Córdova, A., Turcotte-Cardin, V., Yee, Y., Taylor, C., Visuvanathan, S., Babbs, C., Ivakine, E. A., Sled, J. G., Nieman, B. J., Picketts, D. J., & Justice, M. J. (2023). A new mouse model of ATR-X syndrome carrying a common patient mutation exhibits neurological and morphological defects. Human Molecular Genetics, 32(15), 2485–2501. https://doi.org/10.1093/hmg/ddad075