Every cell in a living organism contains the same DNA, yet different genes are turned on or off at specific times and places to guide development. How this process unfolds dynamically — across space and time — remains one of biology’s central mysteries. While the genome’s organization in three dimensions is known to influence when and where genes are activated, we still lack a causal, mechanistic understanding of how physical changes in chromatin structure control gene transcription during development.
DynaTrans (Transcription in 4D) aims to uncover how gene activity is orchestrated in both space and time within the mammalian nucleus. The project brings together three complementary disciplines — molecular genetics, quantitative live imaging, and theoretical physics — to bridge molecular, cellular, and developmental scales of gene regulation. The consortium unites three leading scientists: Thomas Gregor (Institut Pasteur/Princeton University), an expert in quantitative imaging of transcription; Denis Duboule (EPFL/University of Geneva), a pioneer in mammalian developmental genetics; and Gašper Tkačik (IST Austria), a specialist in statistical physics and information theory.
At the heart of DynaTrans lies the ambition to connect chromatin dynamics — the movement and reorganization of DNA and its associated proteins — with transcriptional dynamics, the process by which genes are turned on and off. Using gastruloids (miniature, self-organized embryo-like structures derived from stem cells) as a model system, the project investigates how DNA folds and unfolds during early development, and how this folding determines which genes are expressed and when.
The research is organized in two overlapping phases:
1. Phase I builds a quantitative picture of how gene loci move and interact inside the nucleus during gastruloid development. This involves combining genome-wide methods (such as Hi-C, ATAC-seq, and single-cell RNA-seq) with real-time microscopy of transcription and enhancer–promoter dynamics.
2. Phase II tests causality by directly perturbing the genome and chromatin structure — using CRISPR-based genetic engineering and optogenetic control of chromatin-binding proteins — and by comparing experimental data with theoretical models of chromatin as a dynamic polymer.
Through this integrative experimental-theoretical framework, DynaTrans will reveal how the three-dimensional organization of chromatin determines the timing and coordination of gene activity, providing a predictive, mechanistic model of transcriptional regulation.
Expected impact:
By establishing a unified description of gene regulation across spatial and temporal scales, DynaTrans will profoundly change how we think about genome function in development. The project will deliver conceptual, technological, and computational advances — from live imaging of chromatin architecture to physics-based models of gene expression — with broad implications for developmental biology, systems biology, and precision medicine. The outcomes will pave the way for understanding how genetic information is dynamically interpreted to build complex organisms.
