Project description
A transcription ‘movie’ in multiple scales of time and space
As mammalian embryos develop, an exceptionally complex and well-orchestrated dance occurs involving genetic materials in the nucleus, DNA, and regulatory molecules. The steps of this dance take place over relatively large time and distance scales, and the nuances are difficult to record and study. The ERC-funded DynaTrans project aims to combine optical, molecular-genomic and theoretical tools applied to recently available mammalian pseudo-embryos to shed light on the dynamic mechanisms underlying developmental gene regulation. The work will include tracking transcriptional activation, DNA interactions, and chromatin dynamics in real time and developing mathematical models to simultaneously capture long-timescale chromatin rearrangements and short-timescale movements of genetic regulatory elements and transcriptional activity.
Objective
During mammalian embryogenesis, key events involving DNA and regulatory molecules over seconds and nanometers affect and are affected by, a major reorganization of the genetic material in the nucleus over hours and micrometers. How these scales are spanned and integrated into the course of development remains a major unresolved challenge. Progress in this quest is difficult, either because current model systems suffer from severe technical limitations or because existing analytical approaches probe individual spatial or temporal scales thus ignoring their evolving interactions. Traditional live imaging lacks the spatial resolution to accurately delineate chromosome organization at the scale of genes, while bulk molecular assays are ill-suited for studying development over time. Here, we propose a multi-disciplinary approach to the dynamics of developmental gene regulation to understand the details of the underlying mechanisms and their deployment over time. We combine and apply optical, molecular-genomic, and theoretical tools to recently available mammalian pseudo-embryos, allowing unprecedented precision in developmental staging, a large amount of material, and easy optical access. By focusing on select gene loci we track transcriptional activation and the interactions of distal DNA elements in real-time along with the associated chromatin dynamics using interaction profiles. Our datasets are iteratively distilled into mathematical models of increasing scope, converging towards an integrative dynamic polymer model that simultaneously captures long-timescale chromatin rearrangements as well as short-timescale motions of genetic regulatory elements and transcriptional activity. We then challenge these models via genome editing and temporally defined interventions by building light-controlled tools to affect the chromosome landscape. This project aims to reshape our view of how genes are regulated during mammalian development.
Fields of science
Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC-SYG - HORIZON ERC Synergy GrantsHost institution
75724 Paris
France