We are interested in the function of the chromatin remodelling factor ATRX and how mutations in this factor lead to human disease.
One of the major challenges in the post-genomic era is to understand how the genome is regulated. It has become apparent that chromatin structure is of paramount importance for a wide variety of fundamental nuclear processes including DNA replication, DNA repair and expression of genes encoded by DNA. The ATP-dependent chromatin remodelling factor ATRX has emerged as a key player in each of these processes. The principal aim of the group is to characterise the ATRX protein and understand its function. Children born with mutations in ATRX have a severe X-linked form of syndromal intellectual disability, one feature of which down regulation of alpha globin gene expression (alpha thalassaemia). We have also shown that somatic mutations in this gene give rise to an acquired form of alpha thalassaemia associated with myelodysplasia. ATRX mutations are also a hallmark of a group of cancers that maintain their telomeres by a telomerase-independent mechanism called the Alternative Lengthening of Telomere (ALT) pathway. ATRX with its partner protein DAXX deposit the histone variant H3.3 in a replication independent manner throughout the genome but particularly at tandem repeat sequences such as telomeres. Work from our lab and others has shown the importance of this process in maintaining histone modifications associated with epigenetic memory. It is also important in maintaining genomic stability; in the absence of ATRX DNA secondary structures abound and these are thought to lead to replicative stress and DNA damage. The purpose of our work is to determine the role of this protein in the nucleus and how mutations give rise to seemingly disparate disorders.
David Clynes, Children with Cancer UK
Doug Higgs FRS, Weatherall Institute of Molecular Medicine
Clinical studies and trials
We run a clinical and molecular diagnostic service through which we have collected over 200 affected families. We identify the underlying mutations and through gene expression analysis, methylation studies, enzyme assays and protein structure studies we are defining their functional consequences.