Mechano-Genomics Group Projects
The major themes of research of the mechano-genomics 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.