Université de Strasbourg

Thomas Sexton

Biography - Thomas Sexton

Institute of Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, CNRS and Inserm, France

Thomas Sexton, USIAS Fellow 2022Tom Sexton obtained his PhD from the Babraham Institute (University of Cambridge, UK) in 2008, before performing postdoctoral research in the Institute of Human Genetics in Montpellier. Throughout his career he has been interested in how chromosomes fold up to fit into the cell nucleus, and how this folding can help the right genes be controlled at the right time. He started his group “Spatial organisation of the genome” at the IGBMC in 2014 to pursue this field of research, obtaining an ERC Starting Grant (2015) and the Claude Paoletti Prize (2016).

His current work focuses on how controlling elements far away from genes (enhancers) are able to “find” their appropriate targets, and how all are folded into functional domains, termed topologically associated domains.

Project - Assessing the role of local chromatin dynamics in transcriptional response and DNA repair

01/12/2022 – 30/11/2025

The genome needs to be compacted ~100,000 fold to fit within the cell nucleus, yet still be accessible to the different factors required for gene expression and repair of damaged DNA. Over the last two decades, a lot of progress has been made in understanding the three-dimensional structure of chromosomes. For example, elements (enhancers) that control genes from a distance were found to directly contact their targets. Further, the chromosome is folded into discrete spatial units, termed topologically associated domains (TADs), which delimit the functional range of enhancers. However, mostly due to technological limitations, next to nothing is known about how these structural features behave in real time. Current evidence suggests that they may be transient and dynamic, raising questions as to how they are able to mediate genome functions such as expression control. The question of whether damaged DNA needs to have altered dynamics to facilitate repair is a long-standing and controversial topic.

We have recently optimized a method to fluorescently label specific genetic elements for tracking in live microscopy, and found that whereas exact gene-enhancer spatial separation does not necessarily correlate with expression, local dynamic features do: active genes diffuse more rapidly, and both regulatory elements have more constrained mobility than “neutral” sequence. Further, even “neutral” sequences seem to have locus-specific diffusive properties, which may be linked to function, although no underlying “rules” are known due to a lack of systematic analysis.

In this USIAS project, we propose to more systematically measure chromatin dynamics at multiple regions within the genome and combine with physical modelling to try and understand the principles determining chromatin mobility. With the use of a modular tag system, we will also add reporters and manipulate these same tagged regions to formally assess whether gene expression or DNA damage alters local chromatin mobility and, conversely, whether altered chromatin dynamics affects the ability to regulate gene expression or perform robust DNA repair. This promises to move the field from a 3D to a 4D view of genome regulation and function.

Biography PhD student - Mariia Nazarova

Institute of Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, CNRS and Inserm, France

Mariia Nazarova

Mariia Nazarova obtained her Master's degree in Life Science at the Skolkovo Institute of Science and Technology (Moscow, Russia), with a thesis on the role of long non-coding RNAs in hepatocellular carcinoma. She then joined the Institute of Molecular Pathology (Vienna, Austria) as a Research Assistant on a project exploring the relationship between replication timing and inter-chromosomal translocations, which resulted in a Science paper in 2022 (https://doi.org/10.1126/science.ade4734).

After that, Mariia Nazarova continued her research on chromatin dynamics and started her PhD under the supervision of Thomas Sexton in October 2022, working on the project devoted to deciphering the fundamental principles of genome organization and mobility. Her work combines genomic and imaging techniques in order to find out how different nuclear contexts and epigenetic states affect local chromatin dynamics.


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