François KEPES, PhD —
Rational ab initio engineering of synthetic microbial chromosomes
Topology, dynamics and spatial development of complex biological networks
Digital information storage on DNA.
Brief ResumeFrançois Kepes is a cell biologist. He is currently studying and engineering genome architecture. For this purpose he uses various approaches including molecular, systems and synthetic biology.
François Kepes is a co-founder of the company Synovance which commercialises solutions in synthetic genomics and bio-production. He is a fellow of the National Academy of Technologies of France.
He was a research director at CNRS (1995-2017), an associate professor of biology at École Polytechnique (1992-2004), and recently an invited professor at the Centre for Synthetic Biology and Innovation (CSynBI), at Imperial College London in England. He was the Founding director (2002-2017) of the Epigenomics Project (Genopole), an institute of complex studies. He was the Founding director (2008-10 & 2015-16) of the institute of Systems and Synthetic Biology, at Genopole (iSSB – CNRS, UEVE). He led the « Modelling and Engineering Genome Architecture » team at iSSB (1999-2017). He founded the mSSB Master2 curriculum in France, and co-founded the European ITEMS master program at the Polytehnica of Bucuresti in Romania.
François Kepes is the author of over 130 scientific publications and the editor or author of 22 books and of 14 book chapters. He was awarded the « scientific excellence » prize from 2014 to 2017. He has organized or chaired 2-7 international scientific events per year from 2004 to 2017, including over 40 in Synthetic Biology since 2005. He serves as the editor of four international journals including « Synthetic Biology », and as an expert advisor for European, North- and South-American and Middle-East funding agencies. He acted as the team leader of the first French iGEM team, that was finalist, won a gold medal, and was awarded the first prize of foundational research at MIT in 2007.
Recent Research in a NutshellIn 2002 we pioneered the complex systems description and analysis of networks of transcriptional interactions, which involved some new mathematical developments. In 2003 we uncovered regularities in the positions of co-regulated genes along bacterial and yeast chromosomes. These regularities were interpreted in the framework of a solenoidal model of chromosomes (Fig. 1).
Since then, we showed that this genomic pattern is ubiquitous both phylogenetically (all eubacterial phyla, plus the archae and the yeast that were tested), and functionally (co-regulation, co-function, pathogenicity). To this end we developed and applied new algorithms that can be freely used on the SynBio platform “abSYNTH”.
Importantly, it appeared that Genome Layout and Expression depend on each other via Chromosome folding and Conformation (Fig. 2). This dynamic 3-fold interdependence is key to whole-genome and chassis engineering.
Figure 2. Relation between Genome layout, Genome expression and Chromosome conformation. Genome layout is the respective positioning of co-functional genes. Genome expression means the expression of these co-functional genes. Chromosome conformation refers to DNA folding and the clustering of the co-functional genes. Our approach consists in considering all three aspects at once in a single picture. Definitions: a) Individual gene transcription is modulated by sequence-specific Transcription Factors (TF). A TF binds to its Binding Site (TFBS) in the regulatory region of its target gene(s) to activate or repress its transcription. b) « Co-functional genes » refers to three, not mutually exclusive, possibilities: genes that are co-regulated by the same TF, or encoding proteins from the same complex or from the same metabolic pathway.
The current evidence can be summarized as follows. The positions of co-functional gene sets show proximal or periodical patterns, or combinations thereof. These non-random genome layouts induce defined chromosome 3-D conformations (Fig. 3). Such DNA conformations are both cause and consequence of the clustering of co-regulated genes. By elevating the local concentrations of cognate Transcription Factor (TF) and TF-Binding Site (TFBS), gene clusters improve the overall dynamics of genome function; in particular transcriptional control is much strengthened (70-fold, e.g., lactose operon); and the noise at transcriptional initiation is reduced. Finally, this improved genome function magnifies the effects of genome layout on DNA conformation.
Figure 3. Left, thermodynamically equilibrated non-supercoiled DNA bearing periodic protein-binding sites of different types shown with different colours. Right, supercoiled DNA: a 21kb DNA segment is stretched with a force f=0.8pN, and a supercoiling index sigma=0.033.