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Molecular actions of transcription factor ZFHX3 to drive growth, appetite, and energy expenditure pathways in the hypothalamus S&T28

  • School: School of Science and Technology
  • Study mode(s): Full-time / Part-time
  • Starting: 2022
  • Funding: UK student / EU student (non-UK) / International student (non-EU) / Fully-funded

Overview

NTU's Fully-funded PhD Studentship Scheme 2022

Project ID:S&T28

Obesity is a major contributor to preventable death worldwide and is linked to the development of several diseases including type-2 diabetes, cardiovascular disease, cancer, and even impaired recovery from COVID-19. Overweight and obesity are driven in the brain through the homeostatic control of appetite and energy expenditure (energy balance), but interventions to target these pathways have been remarkably unsuccessful so far. Thus, these physiological processes are crucial to understand in order to develop novel interventions to tackle the obesity epidemic and associated comorbidities.

Zinc finger homeobox-3 (ZFHX3) is a transcription factor implicated in many diseases, and recent work has demonstrated an important role for ZFHX3 in regulating the central circadian clock in the hypothalamus by transcriptional regulation of key neuropeptides. A protein altering variant in human ZFHX3 is associated with low BMI, and in unpublished work we have shown that disruption of ZFHX3 leads to reduced appetite, growth, and lean mass-adjusted energy expenditure in mice. This is accompanied by altered expression of key genes encoding somatostatin, Sst; neuropeptide-Y, Npy; and the orphan G-protein coupled receptor-50, Gpr50; in discrete regions of the hypothalamus and in nutrient sensing tanycyte cells where ZFHX3 is expressed. These genes all contain promotor or enhancer marks and ZFHX3 binding motifs upstream of their coding sequence. Together, this leads to the hypothesis that ZFHX3 drives metabolic phenotype by altering expression of downstream targets in order to regulate whole body growth and energy balance.

The overall aim of this project is to investigate the action of ZFHX3 on these three candidate molecular targets. The project will take advantage of neuronal cell lines that express Sst and Npy and Gpr50 expressing mouse primary tanycytes in the following three arms:

  1. ZFHX3 expression co-localisation with candidate molecular targets will be tested using co-immunohistochemistry / fluorescent in situ hybridisation and/or spatial transcriptomics in mouse brain tissues.
  2. ZFHX3 altered expression of candidate target mRNAs through promotor and enhancer interactions will be tested using molecular tools such as electrophoretic mobility shift assays (EMSAs) to investigate ZFHX3 binding, and luciferase reporter assays to investigate ZFHX3 enhancer / promotor activity on target sequences.
  3. Follow up in vivo experiments will be carried out testing the role of Gpr50 in ZFHX3 expressing tanycyte cells to alter energy expenditure and metabolic phenotype.

Together this project will provide valuable insight to the central regulation of energy balance, in order to target development of future therapeutics.

School strategic research priority

This project aligns with the Centre for Health, Ageing and Understanding Disease (CHAUD), particularly the Health and Wellbeing research theme.

Entry qualifications

For the eligibility criteria, visit our studentship application page.

How to apply

For guidance and to make an application, please visit our studentship application page. The application deadline is Friday 14 January 2022.

Fees and funding

This is part of NTU's 2022 fully-funded PhD Studentship Scheme.

Guidance and support

Download our full applicant guidance notes for more information.

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