The Mechano-Genomics Group was created with the recruitment of G.V.Shivashankar as a Full Professor at the Department of Health Sciences and Technology, ETH Zurich jointly with the Paul Scherrer Institute (PSI). The research laboratory of the group is located at PSI and has started its activities in January 2020. Since January 2021 the mechano-genomics group is part of the Laboratory of Nanoscale Biology (LNB) at PSI.
Our research group is focused on understanding the role of mechano-chemical signals on 3D chromatin organization and function that regulate cell-state transitions. In particular, we study this during cellular ageing and rejuvenation. Furthermore, we explore if alterations in chromatin organization could provide robust biomarkers for ageing related disease diagnostics, including fibrosis, cancer and neurodegeneration. In these studies, we use bio-imaging combined with bio-interfaces, functional genomics and machine learning methods. On the computational side, we collaborate closely with Caroline Uhler’s group at MIT.
The three major themes of research in our group include:
A: Biophysics of mesoscale chromatin states in living cells
DNA is differentially packed into heterochromatin (condensed and repressive) and euchromatin (open and active), determining the gene expression program of living cells. In recent work we showed that such differential packing, regulated by post-translational chromatin modifications, is highly sensitive to extra-cellular mechanical (ECM) constraints, although the underlying principles are unclear. Towards this, we use single cell fluorescence imaging combined with micromanipulation experiments, to map the ultrastructure and dynamics of the mesoscale states of chromatin. In addition, we are exploring if correlative fluorescence and soft X ray tomography could provide additional insights on the biophysical basis of condensed chromatin structure and how they are altered with ECM constraints to regulate gene expression programs.
B: Mechano-genomics of chromatin states during cellular rejuvenation and tissue repair
Cellular ageing results in major alterations in nuclear mechanotransduction pathways, chromatin re-organization and genome programs leading to progressive decline in tissue homeostasis. In recent work, we demonstrated that mechanical signals could partially reprogram and rejuvenate ageing human fibroblasts, although the epigenetic mechanisms are unclear. Towards this we study the cytoskeletal remodelling mechanisms to activate nuclear mechanotransduction pathways and 3D chromatin architecture, using chromosome painting and chromosome conformation assays, in such cell-state transitions during cellular ageing and rejuvenation. In addition, we are exploring if implanting such mechanically reprogrammed patient specific aged cells could provide robust tissue regeneration and wound healing models.
C: Single-cell imaging-AI based chromatin-state biomarkers for early disease diagnostics
Abnormalities in nuclear and chromatin organization are hallmarks of many diseases including cancer. However, quantitative methods to analyse nuclear and chromatin abnormalities for early disease diagnostics are still missing. Towards this, we showed that nuclear and chromatin condensation patterns in human breast tumor biopsies, obtained using fluorescence imaging combined with machine learning, provide robust biomarkers for disease progression. In ongoing studies, using liquid biopsies, we are exploring if such chromatin biomarkers provide robust methods for early disease diagnostics; including fibrosis, cancer and neurodegenerative diseases. Our goal is also to integrate such chromatin biomarkers to miniaturized microfluidic assays combined with mobile phone based fluorescence microscopy for use in personalized treatment models and field trials.
Ongoing clinical trial (Chro-Mark)
In collaboration with the Center for Proton Therapy at PSI, we have started a clinical trial to analyze if chromatin biomarkers in liquid biopsies could help determine the efficacy and toxicity of proton radiation therapy in human patients. Feasibility of such chromatin biomarkers may also help in better patient follow-up and therapy models.
In the above projects, we have multiple openings for PhD students and postdoctoral fellows with a strong background in molecular and cell biology, genomics, bioengineering, advanced light microscopy/image analysis and computational biology.
Senior Scientists associated with the MGG group:
Celestino Padeste is a Chemist specializing on polymer brushes and biointerfaces, and engaged in the development and fabrication of supports for protein crystallography. Currently, he is initiating collaborations with the Mechano-Genomics Group to develop single-cell 3D engineered wells combined with microfluidics for Nuclear Mechanobiology.
Philipp Berger is a Cell Biologist specializing on receptor mediated cell signaling mechanisms. Outside of his main research program, he is initiating collaborations with the Mechano-Genomics Group to develop multi-color labelling strategies for Nuclear Mechanotransduction.
Soichiro Tsujino is a Physicist currently working on the application of acoustic levitation for protein crystallography. Outside of his main research program, he is initiating collaborations with the Mechano-Genomics Group to develop ultrasound based methods to analyze Nuclear Mechanical Homeostasis.
Hosted by the Laboratory of Nanoscale Biology, the Cellular Structural Biology & Bioimaging online symposium brings together top experts in structural biology of dynamic biomolecular complexes, in-situ structural biology, integrative structural and cell biology across scales, and cutting-edge methods development.
October 26 - 27, 2021, online