The Drier Lab for Systems Biology of Cancer: Uncover genomewide dysregulation of regulatory elements behind cancer
Cancer is driven by genetic and epigenetic changes to the DNA. We now know quite well how genetic alterations of genes drive cancer, thanks to extensive mapping efforts. However, we still know very little about the extent and function of genetic and epigenetic alterations at regulatory regions away from genes.
Other than expanding our understanding of gene regulation and dysregulation in cancer, we aim to leverage this knowledge to predict novel therapeutic targets for the development of new drugs, and develop models to predict patient outcome to help guiding treatment plans for cancer patients.
Our scientific approach combines epigenetic profiling, development of computational models and algorithms, and experimental validation. We combine cutting edge experimental techniques with developing new machine learning algorithms and big-data analytical approaches.
We study how genetic and epigenetic alterations of regulatory DNA elements cause cancer or contribute to the disease. We focus on two types of regulatory DNA elements: enhancers (regulating transcription), and CTCF binding sites (regulating chromosomal topology, i.e. the folding of the chromosome in 3D).
Epigenetic topological alterations in cancer
We have previously demonstrated that aberrant DNA methylation of CTCF binding sites in IDH-mutant glioma perturbs chromosomal topology . Normally our chromosomes are divided to multiple topological domains which allow frequent interaction within each domain, but limit interactions across domain boundaries. We demonstrated that in IDH-mutant gliomas, CTCF binding sites at boundaries get methylated, lose CTCF binding, disrupt insulation between adjacent topological domains, and allow aberrant interactions between genes and enhancers. Specifically, this allows activation of the PDGFRA oncogene that cause the cells to become tumorigenic. This groundbreaking model demonstrates that epigenetic and topologic alterations can drive cancer, while highlighting the importance of regulatory DNA alterations.
We are extending this framework to additional types of cancer and of topologic disruptions to test the interplay between metabolism, epigenetics, topology and gene regulation, and how it is dysregulated across different types of cancer.
Genetic dysregulation of DNA regulatory elements in cancer
We develop systematic approaches to integrate genetic, epigenetic, topologic and transcriptional information to study how genetic alterations affect the function of regulatory DNA elements. For example, we have recently uncovered how genetic translocations alter the targets of enhancers to rewire the gene regulatory network into a positive feedback loop . We are now working to extend such approaches to comprehensive analysis of functional regulatory DNA alterations across cancer.
We are currently recruiting talented candidates for MSc, PhD and postdoc positions, as well as Medical School students and undergraduate students for part time projects.
If you are interested email CV and recommendations to firstname.lastname@example.org