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We are part of the Systems Biology community at the Weizmann Institute, with affiliations to the Department of Computer Science and Applied Mathematics and the Department of Biological Regulation.

Epigenomics. Our group is studying the physical interfaces that associate genomic information with mechanisms that interpret it in the nucleus. Such physical mechanisms are in need since only part of the information in the genome is used at any given point in space and time, and since a single (albeit very long) piece of genomic code is used to implement thousands of different functional cell states. The physical interface to the genome’s information include marking and packaging of DNA into chromosomes, the organization of chromosomes into tight three-dimensional nuclear space, and the processes that stabilize and propagate the physical form of the genome across cell divisions. Together these mechanisms broadly define the scope of Epigenomics.

Theory and Experiments. The group is a interdisciplinary mixture of computer scientists, biologists, mathematicians and physicists. We combine extensive computational work with the development of new experimental techniques for studying the epigenomics of complex, heterogeneous cell populations at the population and single cell levels. Our goal is to develop realistic models with parameters that can be quantitatively inferred using novel high throughput sequencing-based experiments. In addition to many projects that are based experimentally in our lab, we are collaborating with several leading experimental groups in the world.

Current research. The group is involved in multiple efforts aimed at understanding the physical organization of chromosomes using Chromosome Conformation Capture (3C) and several of its high throughput implementations (Hi-C, 4C-seq). We wish to first measure and then model the miraculous mechanisms that allow thousands of regulatory elements to target hundreds of genes in a specific, robust and yet dynamic fashion, and while being confined to tiny compartments within the nucleus. Another epigenetic mechanism we are particularly interested in is DNA methylation, which we use as a model for understanding how DNA sequences, epigenetics and gene regulation are tightly affecting each other in the cell. In many cases, we use comparative genomics and epigenomics, and detailed evolutionary models to add another dimension to our studies.

Tumor Heterogeneity. We apply much of the insights we gain from the above efforts to characterize the involvment of epigenetic changes in cancer. We wish to understand how changes to the epigenome affect the cancer phenotype, and to test if epigenetic errors contribute to or caused by the main transitions of normal cells toward cancer. Our approach is inspired by methods and ideas from the theory of evolution. We therefore develop methods to measure tumor heterogeneity and diversity, and model the processes that combine this diversity with selection to drive tumor initiation, progression and response to treatment.