Division of Signaling and Functional Genomics
Prof. Dr. Michael Boutros
A global network of profile similarities to understand complex gene regulatory networks. Heigwer et al., 2023, Cell Systems
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Cellular signaling networks control key decisions during development, health and disease. Genomic approaches such as whole genome sequencing and genetic mapping have identified many genetic variants in signaling components, yet their function and interactions often remain unknown. To address this, we develop and apply functional genomic methodologies to understand context-dependent functions of signaling molecules, to dissect their mechanisms and to discover new vulnerabilities of tumor cells. We perform systematic screens to functionally identify novel components, understand how they are connected and how to interfere with their aberrant regulation in disease. We use genetic and genomic methods to link genotypes to phenotypes, and cell biological approaches to study specific processes and probe underlying mechanisms. Current research interests include:
Wnt signaling networks in development and cancer:
Wnt signaling pathways are required for stem cell maintenance and patterning decisions in all metazoans and are often dysregulated in cancer. We use a spectrum of model systems, from Drosophila to mouse, human cancer cells and organoids, to identify key components and understand the physiological and pathophysiological regulation of Wnt signaling. High-throughput screens and integrative genomic approaches are used to identify and characterize novel Wnt pathway components, identify potential therapeutic targets and chemo-genetic interactions.
Systems genetics, chemical genetics and synthetic lethality in cancer cells:
How genes interact in complex networks to influence phenotypes at the cellular, tissue or organismal level are important questions to be addressed to understand how genetic networks become dysfunctional in disease and how these networks respond to perturbations such as drug treatments. We systematically analyze genetic interactions to dissect genotype-phenotype relationships using single-cell, high-content imaging and multi-omic approaches. We are developing the genomic technologies required for high-throughput screening using RNAi, CRISPR and small molecules, and combining them with novel data integration approaches to generate comprehensive functional maps of cellular processes.
Experimental and computational approaches for high-throughput screening:
Our group is pioneering novel methods for high-throughput genetic and pharmacological perturbation. This includes the development of novel CRISPR and RNAi libraries for use in vivo and in vitro, new image-based phenotyping assays, and combinatorial approaches for genetic and small molecule perturbations. We are also developing new computational tools for automated analysis and visualization of high-throughput screens and integrative analysis of screening results. These include algorithms, software applications for RNAi and CRISPR reagent identification and off-target prediction, and public databases of functional screening data.
FUTURE OUTLOOK:
We are particularly interested in questions that address context-dependent mechanisms of Wnt signaling and approaches to identify novel targets of Wnt pathways in cancer. We will make use of patient-derived organoids and pursue novel targets. As a future aim of our research, we will transfer technologies developed in model organisms using high-dimensional phenotyping to more complex models. Finally, we will continue to develop optimized tools for gene inactivation by precision genome engineering, high-content imaging of organoids, and comprehensive analysis of large-scale phenotypic data.
