The role of neurogenesis and epigenetic modifications for body weight regulation

Supervisors: Tyler Stevenson, John Menzies, Peter Morgan

Project description:

Background: Body weight is regulated over the short and long-term by mechanisms in the brain. Photoperiodic rodent species (i.e. rats/hamsters) are valuable models to study long-term regulation of body weight due to the robust and reliable changes in body weight in response to simple switches in day length. Studies have shown that a critical cell population along the ependymal layer of the third ventricle is essential for the photoperiodic regulation of body weight. A major advance was the discovery that this cell population is a neural stem cell niche and that increased neurogenesis (i.e., the development of new neurons) was associated with reductions in body weight. For example, levels of the neurogenic marker KI67 were significantly increased after short-day induced body weight loss. How the decrease in photoperiod initiates neurogenesis in the hypothalamus is poorly understood. However, there is strong evidence that epigenetic modifications are involved in the generation and maintenance of primordial germ cells. Recent studies in photoperiodic rodents have revealed significant reductions in global hypothalamic DNA methylation and DNA methyltransferase expression during high cell proliferation and body weight loss. Understanding these epigenetic modifications may lead to interventions that can promote the maintenance of optimal body weight.

Aims: The objective of the studentship addresses the BBSRC strategic priority World Class Bioscience. The specific focus will be on the role of an enzyme involved in DNA methylation, DNA methyltransferase 1 (DNMT1), which is expressed in the ependymal layer and shows significantly lower levels of expression when rodents have high neurogenesis and low body weight. Using a range of in vivo, in vitro and cutting-edge genomic manipulations, the studentship will investigate the functional link between DNA methylation, neurogenesis and body weight regulation.

Approach: This project is multi-disciplinary and an integrative project that will take advantage of the biological rhythms groups in the UoA School of Biological Sciences, the UoE Centre for Discovery Brain Sciences and the neuroendocrine energetic group at the UoA Rowett Institute of Nutrition and Health.

Training: This studentship will involve light- and diet-induced changes in hamster body weight. Students will receive directed experience in animal care & Home Office training. Methodological approaches may include cutting-edge methods including CRISPR-Cas9, Next generation bisulfite-sequencing, fluorescence-activated cell sorting, qPCR, immunohistochemistry and hormonal measurements. Students will be encouraged to develop other in vivo, in vitro or in silico approaches. This studentship will expose the student to broad fields of research including: neuroanatomy, bioinformatics, molecular neuroscience, physiology, and animal behaviour. The PIs maintain an open-door policy for trainees and will be actively involved in implementing and refining experimental approaches, interpreting data, locating an industrial partner and planning future work. Students will also be encouraged to engage other scientists in the PIs’ institutes, wider extended networks and to foster their own collaborations. Lastly, the student will attend and present their findings at UK and international conferences.

Relevant Publications:

1. Stevenson TJ, Prendergast BJ. 2013. PNAS.110:16651-16656

2. Shearer KD, et al., 2012. J Neurochem. 122:789-799.

3. Hume C, Sabatier N, Menzies J. 2017. Endocrinol. 158:2200-2211.