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Two PhD Positions on Computational Biophysics

Two PhD Positions on Computational Biophysics
Nuclear mobilities of regulatory hubs in transcriptional control
Molina Lab & Sexton Lab

Reference
IGBMC / PHD MOLINA

Contract type
PHD

Publication date
06/02/2022

Precise control of gene expression accompanying developmental changes is frequently conferred by distal cisregulatory modules (CRMs), such as enhancers, often acting at large genomic distances from their target gene promoters. Recent evidence supports a model of chromatin loops bringing individual enhancers into contact with activated genes, but this is challenged by recent findings. Imaging experiments have shown enhancers at large distances from activated genes, and large multi-CRM-promoter hubs have been identified, which sometimes (but not always) co-associate with clusters of specific transcription factors (TFs). Such hubs have been proposed to create local microenvironments, perhaps via the formation of condensates, whereby regulatory factors can be rapidly exchanged within a high local concentration. How activated genes are functionally recruited to enhancer hubs, how specificity of gene-enhancer nuclear microenvironments are maintained, and how transcriptional firing is ultimately regulated within them, remain unaddressed questions. Most previous studies of 3D chromatin organization overlooked the dynamic biophysical properties of these hubs. Hence, the inherent mobility or diffusion properties of the underlying chromatin at CRMs is largely unknown, in particular in the context of a nuclear microenvironment. We hypothesize that if direct promoter-enhancer juxtaposition is not required for transcriptional firing, then the ability of CRMs to explore their nuclear microenvironment, perhaps via chromatin mobility, could be an important regulatory layer. We propose to combine physical models with advanced live imaging methods to ask: 1) Is the mobility of a CRM affected by its local microenvironment, including clustering with other CRMs or location relative to TF foci? 2) Which factors are responsible for enhancer hub formation or dissociation? 3) What are the consequences of CRM mobility and enhancer clustering on transcriptional output?

Further informations

References
1. Tom Sexton, Giacomo Cavalli. The Role of Chromosome Domains in Shaping the Functional Genome.
Cell 2015: https://doi.org/10.1016/j.cell.2015.02.040.
2. Guilherme M. et al. Precise measurements of chromatin diffusion dynamics by modeling using Gaussian processes. Nature Comms 2022: https://doi.org/10.1101/2021.03.16.435699.
3. Neslihan Avcu, Nacho Molina. Chromatin structure shapes the search process of transcription factors. biorXiv 2016: https://doi.org/10.1101/050146.

Application procedures

Nacho Molina (nacho.molina@igbmc.fr) and Tom Sexton (sexton@igbmc.fr).

Skills

The proposed project will be carried out in close collaboration with the Sexton Lab and will comprise two main tasks: analysis of live-cell imaging using time-lapse microscopy and developing biophysical models of chromatin dynamics and TF diffusion, binding and condensate formation. The candidate is expected to have a strong background in physics, mathematics and programming.