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Structural mechanism of signal-dependent gene transcription


Department of Chemistry

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Prof D Panne No more applications being accepted Competition Funded PhD Project (Students Worldwide)
Leicester United Kingdom Biochemistry Molecular Biology Structural Biology

About the Project

The control of gene transcription is the main regulatory step for cellular gene regulation. Transcriptional activation is triggered by signal-dependent assembly of transcription factor (TF) and co-activator complexes on enhancers to initiate epigenetic modification, local remodeling of chromatin, and, ultimately, recruitment of the RNA polymerase II preinitiation complex (RNAPII, PIC) to promoters. Over the last 50 years, great progress has been made, using X-ray crystallography, cryo-electron microscopy (cryoEM), biochemical and single-molecule methods, in our understanding of structures and functions of individual TFs, coactivators, components of the PIC, and RNA polymerase itself. However, it is not understood how these components work together in space and time, and how cellular signaling controls transcriptional activation,

One of the best-understood model systems for metazoan gene regulation is found in the innate immune system, which is crucial to limit pathogen infections. In the innate immune system, several groups of pattern-recognition receptors induce different signalling pathways leading to production of a variety of antiviral molecules, including type I interferons (IFNs) and proinflammatory cytokines. Previous work from the Panne laboratory has revealed mechanistic and structural insights into how the interplay between cellular signalling and TF activation, controls the function of the co-activator (Ortega et al., Nature 2018).

It is now important to ask how assembly of such complexes controls gene expression. The IFN enhancer system is particularly suitable for structural studies due to its naturally compact organization (about 100 base-pairs) and the proximity of the enhancer DNA elements to the +1 transcription start site. The IFN enhancer is recognized by four activators which synergistically recruit coactivator CBP/p300, a modular protein containing several well-defined domains, and CBP/p300, in turn, is believed to recruit components of the PIC and RNAPII. CBP/p300 is a central player in transcription activation, believed to interact with more than 400 TFs including important tumour suppressors (such as Fos/Jun, MYC, NFkB, p53 and BRACA1). Interaction of p300 with oncogenes such as BRD4-NUT results in an aggressive subtype of lung and head and neck cancer, called NUT midline carcinoma. BRD4-NUT binds to and activates p300 resulting in chromatin hyperaceylation and dysregulation of genome expression.

Recent developments in cryo EM and advances in the structural understanding of RNAPII and PIC now make it realistic to study the entire process of transcription activation, including recruitment of TFs to the enhancer, recognition of the TF surfaces by the coactivator CBP/p300, and, ultimately, recruitment of the PIC components (more than 55 polypeptides) and RNAPII.

The overall focus of the project is to use, the well-defined, natural, compact IFN enhancer to gain mechanistic insights into the assembly of the multicomponent molecular machinery that controls transcriptional activation. Understanding the detailed mode of how enhancers control transcriptional activation will aid in the development of new pharmacological approaches in cancer and other critical human diseases. This is particular important for developing new anti-cancer drugs, because classical tumour suppressors are difficult to target with small-molecule drugs.

The first major aim of this project is to reconstitute the enhancer DNA with two flanking nucleosomes. We will study recruitment of the enhanceosome complex using biochemistry and cryoEM. The resulting complexes will be purified and imaged by cryoEM and single particle reconstruction. Having access to a biochemically well-defined model system will provide a unique opportunity to study how at a structural level how an enhancer controls gene regulation.

Entry requirements:

• Those who have a 1st or a 2.1 undergraduate degree in a relevant field are eligible.

• Evidence of quantitative training is required. For example, AS or A level Maths, IB Standard or Higher Maths, or university level maths/statistics course.

• Those who have a 2.2 and an additional Masters degree in a relevant field may be eligible.

• Those who have a 2.2 and at least three years post-graduate experience in a relevant field may be eligible.

• Those with degrees abroad (perhaps as well as postgraduate experience) may be eligible if their qualifications are deemed equivalent to any of the above

• University English language requirements apply. https://le.ac.uk/study/research-degrees/entry-reqs/eng-lang-reqs/ielts-65

For further information please contact [Email Address Removed]

Application advice:

To apply please refer the application instructions at https://le.ac.uk/study/research-degrees/funded-opportunities/bbsrc-mibtp

You will need to apply for the PhD place and also submit your online application notification to MIBTP. Links for both are on the above web page.

Project / Funding Enquiries: For further information please contact [Email Address Removed]

Application enquiries to [Email Address Removed]


Funding Notes

All MIBTP students will be provided with a 4 years studentship.
Tuition Fees at UK fee rates
- a tax free stipend of at least £15,295 p.a (to rise in line with UKRI recommendation)
- a travel allowance in year 1
- a travel / conference budget
- a generous consumables budget
- use of a laptop for the duration of the programme
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