Project summary: Precise control of gene expression accompanying developmental changes is frequently conferred by distal cis-regulatory 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?
Methodology and required 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 should hold a M.Sc. degree in a relevant field with a strong background in physics, mathematics and programming. Proven research experience in computational biophysics, statistical mechanics or computational biology is expected. A strong motivation and a good capacity to work in a multidisciplinary team are also important. English is the communication language in the team.
Application: To apply, send a single pdf file with your CV, a motivation letter and the contact information of at least two references to Nacho Molina ([Email Address Removed]).
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