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EASTBIO (College of Science and Engineering) Deciphering How Transcription Factor Condensate Formation Directs Cell Identity by Transcriptional Regulation

The University of Edinburgh

Qualification Type: PhD
Location: Edinburgh
Funding for: UK Students, EU Students
Funding amount: Not Specified
Hours: Full Time
Placed On: 25th October 2021
Closes: 16th December 2021
 

Applications accepted up to Thursday 16th December 2021, 5pm 

1st Supervisor: Professor Ian Chambers (University of Edinburgh) 

Other Supervisors: Dr. Davide Michieletto (University of Edinburgh)

About the Project

Cell identity is controlled by transcription factors (TFs) that organize the 3D connections within chromatin, thereby regulating cell specific gene transcription. Recent evidence suggests that TFs may operate via liquid condensates or hydrogels with ill-defined viscoelastic properties. In pluripotent embryonic stem cells (ESCs) the TF NANOG directs ESC self-renewal efficiency in a dose dependent manner. NANOG contains a DNA binding homeodomain and a low complexity domain in which every 5th residue is a tryptophan (the WR). Both homeodomain and WR are required for NANOG function. While the homeodomain binds DNA, the WR mediates interactions with partner proteins. Mutagenesis indicates that WR is required for regulating transcription of NANOG target genes, for interaction of NANOG with partner proteins, including RNAP2, and for efficient ESC self-renewal. NANOG also forms hydrogels and residues in WR mediating the above functions are required for gel formation.

This project will examine the following aims:

  1. Biophysical properties of NANOG hydrogels. Microrheology (a soft matter physics technique using microscopy to characterize the material properties of generic complex fluids) will quantify the viscoelasticity of purified NANOG at different concentrations and in different conditions, including high DNA concentrations mimicking the intracellular environment.
  2. 3D connections of NANOG to chromatin. Looking from target genes, the 3D connections mediated by NANOG will be determined by comparing ESCs carrying wild-type NANOG or debilitating WR mutants.
  3. Mutational analyses.Some WR NANOG mutants may have differential effects on cell identity and proliferation. Microrheology and 3D interaction analyses will be conducted on such mutants to uncover the basis of such differences.

This project will quantitatively link the biophysical properties of TF (NANOG) condensates to cell function.

Funding Notes

UKRI-funded studentships are open to students worldwide and will cover tuition fees at the UK rate, plus a stipend to support living costs and an annual research grant of £5,000 for the first three years of the PhD research. For further details on funding eligibility and how to apply, please see link below.

Click here to APPLY NOW 

The EASTBIO team will run a series of 1-hour online sessions in November/December, open to applicants who have queries about the application process. Please view EASTBIO How to Apply webpage for details. 

Unfortunately due to workload constraints, we cannot consider incomplete applications.

The School of Biological Sciences is committed to Equality & Diversity www.ed.ac.uk/biology/equality-and-diversity

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