Regulatory DNA sequence variants in childhood diseases

Human diseases are increasingly being understood at the molecular level and to date most pathological sequence variants have been linked to protein coding mutations. DNA mutations in non-coding regions of the genome that interact with transcription factors (TFs) can also cause human disease, although the extent to which this occurs is still unknown. Our group is using comparative genomic approaches (experimental and computational) to understand disease causing variants in the human genome. By investigating the biology and evolution of gene regulation, we are working towards understanding, diagnosing and predicting human disease.

Epigenetics and evolution of the inflammatory response in Endothelial Cells

Mammalian cells undergo large-scale and rapid alterations in gene expression programmes during the response to inflammation. The role of gene regulatory networks in orchestrating both the timing and the localization of inflammation responsive gene expression changes are of great interest. Vascular endothelial cells (ECs) line all arteries, veins and capillaries. Their inflammatory activation contributes to cardiovascular diseases (CVD) such as atherosclerosis and thrombosis. A barrier to understanding inter-individual differences in vascular inflammation is that little is known about the gene regulatory elements that control the expression of inflammatory genes. Importantly, more than 80% of the variation in human disease traits is due to variants (i.e. DNA differences between individuals) located in non-coding regions of the genome. Understanding the genetic basis of disease susceptibility will allow us to identify patients that are most at risk of death or disability from atherosclerotic disease and will facilitate personalized medicine (including enhanced monitoring, altered therapy or lifestyle modification for those at risk).

Dissecting the functional significance of topoisomerase II beta in cancer and development

Type II topoisomerases (Top2) play critical roles in genome organization, DNA replication, and gene transcription and are among the most frequently targeted enzymes in cancer chemotherapy. Type II topoisomerases (TOP2) regulate DNA topology by generating transient double stranded breaks (DSBs) during replication and transcription. TOP2A is essential for cell proliferation, and its paralog TOP2B is ubiquitously expressed and required for rapid post-mitotic gene activation. TOP2 poisons are successfully used to treat leukemia, yet paradoxically their use can also lead to therapy-related acute myeloid leukemia. TOP2B is highly expressed in normal hematopoietic stem cells (HSCs) and leukemia initiating cells (LICs). TOP2Bs expression level directly influences the mutagenic effect of TOP2 poisons, yet its DNA binding profile, protein-protein interactions, and DSB-making potential have not been characterized in LICs. We recently found that TOP2B physically interacts with several members of the cohesin complex. This raises the possibility that TOP2B-mediated DNA damage occurs widely at cohesin-bound genomic regions. Our overarching goal is to understand how TOP2B contributes to DNA aberrations in leukemia and understand is biology function during development and cell differentiation.

Modeling of human genome innovations

Evolutionary conservation of genes, TF-DNA interactions, pathways, etc is a powerful way to uncover molecular function. With the exponential increase in the number of available genomes and highthroughput experimental and computational methods to study them, we are able to detect species-specific genome innovations. Due to the huge success of using evolutionary conservation and model organisms to identify molecular function, it is often the species-specific genes and regulatory regions that are less well understood. Repetitive elements for example are a potent source of both gene and gene regulatory innovation. On a case by case basis our lab will undertake the modelling and deep exploration of human-specific genome innovations that directly impact novel biology and human disease