Search Talks

We start by demonstrating that numerical methods do not necessarily converge to entropy or admissible weak solutions of the Euler and Navier-Stokes equations of fluid dynamics on mesh refinement due to appearance of eddies at smaller and smaller scales. As an alternative, we revisit the concept of statistical solutions which are time-parametrized probability measures, consistent with the fluid evolution. We empirically show that the same numerical methods converge to a statistical solution and also derive verifiable sufficient conditions under which this convergence can be made rigorous. Numerical experiments illustrating interesting properties of statistical solutions are also presented. We conclude by showing how state of the art generative AI models (conditional diffusion) can significantly lower the cost of computing statistical solutions while maintaining accuracy.

Alterations in nuclear and chromatin organization are hallmarks of cellular aging and many aging related diseases including cancer and neurodegeneration. However, quantitative methods to analyse subtle alterations in chromatin states to understand cell-state transitions and for early disease diagnostics are still missing. In this talk, I will first describe our AI-based chromatin imaging biomarker platform. I will then demonstrate the sensitivity of this platform to trace tumour progression and neurodegeneration using tissue biopsies. Furthermore, I will describe our ongoing clinical trials, using AI-based chromatin biomarkers in blood biopsies, for early disease diagnostics and for tracing the efficacy of therapeutic interventions in personalized and precision medicine. Finally, I will introduce a major global public health project that we have initiated to develop a chromatin imaging atlas of human blood cells in health and disease.

It is well established that chromosome territories are non-randomly organized in the interphase nucleus, with gene poor chromosome territories proximal to the nuclear periphery, while gene rich chromosome territories are closer to the nuclear center. Such an organization is conserved in evolution. We showed that the depletion of the nuclear envelope proteins i.e, lamins, not only induces chromosomal instability but also destabilizes chromosome positioning in otherwise diploid colorectal cancer cells. Remarkably, the combined loss of lamins and Emerin perturb chromosome territory and gene loci dynamics in the interphase nucleus. Furthermore, nuclear envelope proteins are essential for relaying mechanical signals into the nucleus, since cells cultured on softer substrates showed a striking change in the spatial organization of chromosome territories in an Emerin-Lamin dependent manner. Taken together, our studies reveal an overarching role for nuclear envelope proteins, in the maintenanc...

3D organization of eukaryotic genomes scales from nucleosomes to loops, chromatin domains and chromosome territories. Given the hierarchical nature of this organization we explored the dependence of higher order genome organization on nucleosome positioning across the genome. I will discuss the mechanism by which ATP-dependent chromatin remodeller, ISWI slides nucleosomes to position them regularly and what are the consequences of perturbing nucleosome positioning across the genome on higher order genome organization.

In eukaryotic cells, the nucleosome core particle (NCP) forms the basic unit of the genetic architecture. In NCPs, genomic DNA is tightly wound around an octameric core of histone proteins, much like thread wrapped around a spool. Recent experiments have shown that nucleosomes are highly dynamic, and often unwrap in an asymmetrical fashion at high ionic strengths, or in response to mechanical perturbations. By developing a sequence-specific coarse- grained model for DNA-protein complexes, which recapitulates various aspects of nucleosome structure and dynamics, we show how sequence-specificity of DNA-protein interactions is critical for nucleosome plasticity. Our force-field also captures the two-stage unwrapping observed in single-molecule pulling experiments. We further show that histone tails, which are hotspots for post-translational modifications, play a remarkable role in modulating the extent, as well as the direction of unwrapping. Our observations could set the stage for under...

Human silencers have been shown to exist and regulate developmental gene expression. However, the functional importance of human silencers needs to be elucidated, such as whether they can form “super-silencers” and whether they are linked to cancer progression. Here, through interrogating two putative silencer components of FGF18 gene, we found that two nearby silencers can cooperate via compensatory chromatin interactions to form a “super-silencer”. Furthermore, double knockout of two silencers exhibited synergistic upregulation of FGF18 expression and changes of cell identity. To perturb the “super-silencers”, we applied combinational treatment of an EZH2 inhibitor GSK343, and a REST inhibitor, X5050 (“GR”). We found that GR led to severe loss of TADs and loops, while the use of one inhibitor by itself only showed mild changes. Such changes in TADs and loops were associated with reduced CTCF and TOP2A mRNA levels. Moreover, GSK343 and X5050 synergistically upregulated...

The role of telomeres in cellular and organismal physiology including ageing and cancer is commonly appreciated. However, intriguingly, the molecular impact of telomeres in human cells has been largely limited to the subtelomeres (~10 Mb from telomeres). Questioning this paradigm we found telomere dependent molecular mechanisms affect chromatin across the genome defining functional outcomes ranging from tumor cell immunity to neurogenesis.