Professor of Clinical Genetics
- Consultant Physician
Chromatin remodelling factors in human disease
Chromatin remodelling factors in human genetic disease.
The principal aim of the group is to characterise the ATRX protein; germline mutations in the underlying gene give rise to a severe X-linked form of syndromal intellectual disability one feature of which is alpha thalassaemia. We run a clinical and molecular diagnostic service through which we have collected over 200 affected families. We identify the underlying mutations and through microarray gene expression analysis, methylation studies, enzyme assays and protein structure studies we are defining their functional consequences. This clinical work also informs our research which is to both understand the function of this protein and understand how mutations lead to disease. Recent work has shown that ATRX with the histone chaperone DAXX remodels chromatin by replacing canonical histones with the histone variant H3.3 and that this role is important in maintaining epigenetic memory and patterns of gene expression.
In the last 5 years it has been shown that ATRX acts as a tumour suppressor. Somatic mutations in ATRX are observed in a group of cancers which maintain their telomere length not by reactivating telomerase as is seen in 85% of cancers, but using homology directed repair, a process known as Alternative Lengthening of Telomeres (ALT). We have shown that re-expressing ATRX leads to repression of ALT and this has opened up a new area of research which we are exploring in collaboration with Dr David Clynes (Dept of Oncology)
A gain-of-function single nucleotide variant creates a new promoter which acts as an orientation-dependent enhancer-blocker.
Bozhilov YK. et al, (2021), Nat Commun, 12
An evolutionarily ancient mechanism for regulation of hemoglobin expression in vertebrate red cells.
Miyata M. et al, (2020), Blood, 136, 269 - 278
Genetic and functional insights into CDA-I prevalence and pathogenesis.
Olijnik A-A. et al, (2020), J Med Genet
Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data.
Aitken S. et al, (2019), Am J Hum Genet, 105, 933 - 946
ATRX Contributes to MeCP2-Mediated Pericentric Heterochromatin Organization during Neural Differentiation.
Marano D. et al, (2019), Int J Mol Sci, 20