Roles in Cancer and Disease
Although our work is rooted in basic science, because of the central importance of the systems we work on, everything that we do has direct implications in health, disease and cancer.
Enhancer mutations in disease and cancer
Highly transcribed regions of the genome accumulate mutations, which can cause disease. As active enhancers are transcribed into eRNAs, clusters of mutations also accumulate around enhancers, and mutations within enhancers are found to occur very frequently in a number of complex and common diseases and in cancer. Mutations at enhancers can drive disease in a variety of ways. For example, creation of new binding sites for transcription factors can de-regulate expression of genes whose expression is controlled by the enhancer. However, a large proportion of mutations within enhancers do not affect transcription factor binding. One possibility is that their ability to cause disease arises from changes to eRNAs transcribed from the enhancer. However, as eRNAs do not code for proteins, mutations will not directly affect protein structures, so the reasons for their disease-related outcomes are unclear. A key goal of our group is to understand how changes to eRNAs caused by mutations can result in disease.
We are collaborating with the Cooper-Knock Lab at the Sheffield Institute for Translational Neuroscience to explore the effect of novel enhancer mutations in Amyotrophic lateral sclerosis (ALS, also called motor neuron disease)..
CBP domain model showing structures and disordered regions (A) and domain organization (B). C-D) Distribution of CBP mutations in cancer (cBioPortal, C) compared to mutiatons with no disease phenotype (ExAC, D); cancer mutations cluster within TF binding and catalytic domains.
How do disease-related mutations at enhancers cause disease? One possibility is that they de-regulate the activity of epigenetic enzymes.
CBP in cancer and disease
CBP is recognised as a tumour suppressor - a protein whose normal function is required prevent malignancy. In fact, CBP mutations are found in over 40% of diffuse large B-cell lymphomas. Whilst mutations in diverse cancers are distributed throughout CBP, they tend to cluster in discrete domains responsible for transcription factor binding and, in particular, within the catalytic histone acetyltransferase domain.
CBP plays absolutely critical roles in regulating healthy development. Germ line mutations in CBP drive the developmental disorder Rubinstein Taybi Syndrome (RTS), estimated to occur in 1 in 125,000-300,000 births. RTS is characterised by delayed development, short stature, moderate to severe learning difficulties, distinctive facial features, and broad thumbs and first toes. RTS patients also suffer from an increase risk of cancer. RTS is caused by haploinsufficiency of CBP - mutations only occur in one copy of the CBP gene but the consequent reduction in the activity of CBP in cells is enough to cause the disease.