Cohesin is an evolutionarily conserved multi-protein complex that belongs to the structural maintenance of chromosomes protein family. It can topologically entrap DNA molecules mediating sister chromatid cohesion, a function important for accurate chromosome segregation and DNA replication/repair. It has been recently discovered that cohesin can generate and maintain DNA loops by an ATPase-dependent in cis DNA tethering activity, called loop-extrusion, critical for organising chromatin architecture and regulating gene transcription, and as such thought to be important for cell differentiation and development. The molecular mechanisms by which the cohesin complex achieves these key cellular functions remain to be fully elucidated. Mutations in genes coding for cohesin and its regulators lead to a class of developmental disorders collectively called “cohesinopathies” and have been found in several types of cancer. Nonetheless, the pathogenesis of these devastating human diseases is poorly understood.
Objectives of the research program
The CohesiNet research program aims to:
1) obtain mechanistic insights into key cohesin functions (chromosomal cohesion and chromatin loop extrusion)
2) identify and analyse novel cohesin regulators
3) elucidate how pathogenic mutations alter the functions of cohesin and its regulators
4) discover cellular pathways and developmental trajectories altered in cohesinopathies.
Innovative aspects
Innovative aspects of the CohesiNet research program include a synergistic combination of complementary experimental approaches in biochemistry, structural biology, molecular and cell biology, genomics and biophysics to fulfil the following tasks:
1) in vitro reconstitution and structural analysis of chromatin loop extrusion by cohesin and its regulators with cutting-edge fluorescence and cryo-electron microscopy methodologies
2) in vivo visualisation of loop extrusion during DNA repair by highly innovative time-lapse super-resolution bioimaging techniques
3) biophysical studies of cohesin-DNA interactions at the single molecule level, pushing the limit of correlative optical tweezers-fluorescence microscopy
4) development of induced pluripotent stem cell (iPSC)-based models of cohesinopathies with the use of an advanced cell differentiation screening platform.