Periodic Reporting for period 1 - DynaTrans (Transcription in 4D: the dynamic interplay between chromatin architecture and gene expression in developing pseudo-embryos)
Reporting period: 2024-05-01 to 2025-10-31
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.
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.
During the initial phase of DynaTrans, the consortium established the conceptual, experimental, and technological foundations required to study transcriptional dynamics in mammalian systems with quantitative precision. The first major effort focused on adapting the gastruloid model — three-dimensional aggregates of mouse embryonic stem cells that mimic early stages of embryonic development — into a robust and reproducible system for quantitative analysis.
Traditionally, live imaging of mammalian development has been limited by the fragility and opacity of the embryo. To overcome these barriers, the DynaTrans team has developed a new generation of quantitative live-imaging technologies and data-driven analytical pipelines. These approaches allow researchers to follow in real time how gene activity, chromatin organization, and tissue morphogenesis evolve together during development. The consortium has demonstrated that gastruloids can serve as an experimental system in which transcription, gene-expression dynamics, and morphogenetic processes can all be measured and perturbed quantitatively — a major step forward for the field.
Three recent publications by the DynaTrans partners document these advances, showing that:
1) Mammalian gastruloids can be embedded in controlled physical environments, enabling systematic investigation of how mechanical constraints affect gene-expression patterns and symmetry breaking.
2) Long-term live imaging can now capture transcriptional activity and tissue morphogenesis simultaneously, providing access to dynamic processes that were previously inaccessible in mammalian models.
3) Quantitative analysis tools developed within the project allow reproducible comparison of biological dynamics across conditions and laboratories, laying the groundwork for standardized, physics-based approaches to developmental biology.
In parallel, theoretical work within DynaTrans has advanced models linking chromatin dynamics to transcriptional bursting and enhancer–promoter communication. Using concepts from polymer physics and information theory, these efforts aim to extract predictive principles from the data and to identify universal rules governing the flow of genetic information in time and space.
The experimental and theoretical strands of the project are now converging. The imaging technologies and gastruloid assays developed by the consortium provide the first comprehensive platform to measure how genome architecture and gene activity co-evolve in a developing mammalian system. This progress confirms the technical feasibility and transformative potential of the DynaTrans program.
Traditionally, live imaging of mammalian development has been limited by the fragility and opacity of the embryo. To overcome these barriers, the DynaTrans team has developed a new generation of quantitative live-imaging technologies and data-driven analytical pipelines. These approaches allow researchers to follow in real time how gene activity, chromatin organization, and tissue morphogenesis evolve together during development. The consortium has demonstrated that gastruloids can serve as an experimental system in which transcription, gene-expression dynamics, and morphogenetic processes can all be measured and perturbed quantitatively — a major step forward for the field.
Three recent publications by the DynaTrans partners document these advances, showing that:
1) Mammalian gastruloids can be embedded in controlled physical environments, enabling systematic investigation of how mechanical constraints affect gene-expression patterns and symmetry breaking.
2) Long-term live imaging can now capture transcriptional activity and tissue morphogenesis simultaneously, providing access to dynamic processes that were previously inaccessible in mammalian models.
3) Quantitative analysis tools developed within the project allow reproducible comparison of biological dynamics across conditions and laboratories, laying the groundwork for standardized, physics-based approaches to developmental biology.
In parallel, theoretical work within DynaTrans has advanced models linking chromatin dynamics to transcriptional bursting and enhancer–promoter communication. Using concepts from polymer physics and information theory, these efforts aim to extract predictive principles from the data and to identify universal rules governing the flow of genetic information in time and space.
The experimental and theoretical strands of the project are now converging. The imaging technologies and gastruloid assays developed by the consortium provide the first comprehensive platform to measure how genome architecture and gene activity co-evolve in a developing mammalian system. This progress confirms the technical feasibility and transformative potential of the DynaTrans program.
Before DynaTrans, quantitative measurements of gene activity in mammalian systems were extremely limited, as live imaging and reproducible control of experimental conditions were technically difficult to achieve. In particular, collecting high-statistics, reproducible datasets comparable to those available in simpler model organisms such as Drosophila had remained out of reach.
Through the development of dedicated imaging technologies, standardized culture methods, and quantitative analysis pipelines, DynaTrans has now rendered mammalian gastruloids a tractable and reproducible system for measuring gene-expression dynamics in real time. This establishes, for the first time, a platform that allows the study of transcriptional regulation in complex mammalian contexts with the same quantitative rigor long available in classical model systems.
Through the development of dedicated imaging technologies, standardized culture methods, and quantitative analysis pipelines, DynaTrans has now rendered mammalian gastruloids a tractable and reproducible system for measuring gene-expression dynamics in real time. This establishes, for the first time, a platform that allows the study of transcriptional regulation in complex mammalian contexts with the same quantitative rigor long available in classical model systems.