Schaerli Group

Synthetic gene regulatory networks for pattern formation

During embryonic development, cells acquire different identities, depending on their spatial positions. This developmental process is called pattern formation. The molecular details of pattern formation are complicated, but are thought to be governed by general principles such as the use of morphogen gradients to provide positional information. We build, study and model synthetic gene regulatory networks to improve our understanding of such general principles.

Synthetic gene regulatory networks for pattern formation. Bacterial lawns carrying a synthetic network display circular patterns as a function of chemical gradients from central paper disks (white).

Relevant publications:

Schaerli, Y., Munteanu, A.Gili, M.Cotterell, J.Sharpe, J.Isalan, M. (2014) A unified design space of synthetic stripe-forming networks, Nat. Commun., 5:4905

Perez-Carrasco, R., Barnes, C. P., Schaerli, Y., Isalan, M., Briscoe, J., Page, K. M. (2017) The power of the AC-DC circuit: Operating principles of a simple multi-functional transcriptional network motif, arXiv, doi: 1708.04593v2 [q-bio.MN]

Evolution of gene regulatory networks

What constrains the evolution of gene regulatory networks? What makes a gene regulatory network robust to mutations and/or evolvable? How does the regulatory mechanism of a network influence its evolution? How can gene regulatory networks change extensively, while maintaining overall circuit output? How do mutations in gene regulatory networks interact to produce novel phenotypes? What happens after a gene has been duplicated?

Evolution of gene regulatory networks. Multiple genotypes give rise to the same phenotype. Adapted from Crombach et al., Mol. Biol Evol., 2016

We have several ongoing projects where we address such questions by performing molecular evolution experiments with synthetic gene regulatory networks in E. coli.

One of the project is funded by a SNSF project grant.

Relevant publications:

Schaerli, Y., Jimenez, A., Duarte, J. M., Mihajlovic, L., Renggli, J., Isalan, M., Sharpe, J., Wagner, A. (2017) Mechanistic causes of constrained phenotypic variation revealed by synthetic gene regulatory circuits, BioRxiv, doi: 10.1101/184325

Duarte, J. M., Barbier, I., Schaerli, Y. (2017) Bacterial microcolonies in gel beads for high-throughput screening of libraries in synthetic biology, ACS Synthetic biology, doi: 10.1021/acssynbio.7b00111

Schaerli, Y., Isalan, M. (2013) Building synthetic gene circuits from combinatorial libraries: screening and selection strategies, Mol. BioSyst., 9:1559-1567

Robustness, cryptic genetic variation and innovation in transcription factor binding

In collaboration with Prof. Payne, ETH Zurich and Prof. Wagner, University of Zurich.

Mutational robustness is a striking and widespread property of biological systems. One consequence of this robustness is that genetic diversity may accumulate in transcription factor binding sites. Such diversity is often referred to as cryptic because it does not manifest as phenotypic diversity unless an environmental or genetic perturbation disrupts the function of the cognate transcription factor. What is the mutational robustness of transcriptional binding sites? How is cryptic genetic diversity accumulated? Does cryptic genetic variation in transcription factor binding sites facilitate evolutionary innovation?

We are using a synthetic gene regulatory circuit in E. coli, molecular evolution experiments and computational modelling to address these questions.

This project is funded by a IPhD grant of SystemsX.ch.

Relevant publication:

Payne, J.L. and Wagner, A. (2014) The robustness and evolvability of transcription factor binding sites. Science, 343, 875-877