Typas Group
Dissecting bacterial lifestyle and interspecies interactions with systems approaches
Figure 1: High-throughput phenotypic screens are used to identify gene function and map pathway architecture (Typas et al., Nat Methods 2008; Nichols et al., Cell 2011).
Figure 2: Two novel niche-specific lipoproteins control peptidoglycan synthesis from the outside of the sacculus (Typas et al., Cell 2010).
Figure 3: Integration of different large-scale datasets.
Previous and current research
Bacteria are one of the most abundant forms of life, colonize diverse environments and usually outnumber their hosts. The recent explosion of genomic sequence information provides the first step towards a better understanding of diverse bacteria, but also makes it imperative to develop large-scale phenotyping approaches to characterize functions of the numerous novel genes and to map them within pathways.
Research pioneered in yeast indicates that some of the most powerful global phenotyping approaches are based on scaling up long-standing concepts in biology. Epistasis-genetic interactions assess how the function of one gene depends on the function of a second gene; chemical genetic interactions measure how the function of one gene affects cellular responses to chemical stress. Scaling up these concepts to the genomic level has lead to unprecedented insights on yeast biology. We have developed quantitative high-throughput versions of these global approaches in E. coli, and used them to obtain mechanistic understanding of key aspects of its envelope function and architecture.
The bacterial envelope is sandwiched between two membranes in gram-negative bacteria and constitutes the interface of the bacterium to the environment. This compartment acts as a protective barrier for the bacterium, but also allows it to sense changes in and communicate with its environment, and is vital for pathogenesis, cell morphogenesis and cell developmental programs. Although many envelope structural components have been characterized, we often have limited information on how their biosynthesis and transport are interconnected, regulated, and/or linked to the overall status of the cell, how the organism senses perturbations and how signals are transduced to achieve homeostasis.
Working at the intersection between systems genomic biology and mechanistic molecular biology, we have discovered key missing players of major envelope components, uncovered niche-specific regulation of conserved envelope processes, identified linking proteins that allow coordination between processes and mapped network rewiring under different stresses. Specific examples of the biological stories we have uncovered include: i) identification of the first regulators controlling peptidoglycan synthesis from outside of the cell, thereby providing an opportunity for outer membrane status to influence the fundamental shape-forming structure in bacterial cells (Figure 2); ii) the discovery of a new player that orchestrates outer membrane constriction during cell division; iii) a mechanism to transduce information about cell size/shape to the transcriptional machinery; iv) a mechanism to control the activity of lipoproteins.
Future projects and goals
Although we will continue working on some of the biological aspects or our earlier findings on gene function and pathway architecture in the E. coli envelope, our main goal is to expand our efforts in two directions. First, we want to develop analogous high-throughput methods for other bacteria. This will enable us to generate comprehensive interaction datasets in different bacteria, enrich them with other available genome-wide resources and ultimately use them to create inferences about common and individual characteristics of biology in those organisms. Second, we plan to expand this technology to report on more social characteristics of bacteria. This will enable us to probe interspecies interactions and interactions with the host, shedding light on different mechanistic aspects of these interactions. Our specific aims include the following:
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generation of global genetic and chemical genetic interaction profiles for different pathogen and commensal bacteria; integration with other available global phenotyping data (Figure 3)
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cross-species comparisons to map key features of divergence in the organization of the bacterial envelope
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development of high-throughput approaches to study bacterial interspecies interactions and bacterial-host interactions
10 years of the human genome
EMBL scientists mark a decade since the first draft human genome sequence. Click on image to play. Duration: 6 mins.