Project ID CM-HD2024_37


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Basic & Medical Biosciences, Department of Medical & Molecular GeneticsWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Basic & Medical Biosciences, Department of Medical & Molecular GeneticsWebsite

Making good fat to last a lifetime

The stem cells that can become fat cells (adipose precursor cells or APCs) are generated in early life. The size of this pool in each location remains fairly constant throughout life, but some people have a larger pool of APCs in some depots than others, and this determines how and where their fat expands. If the APC pool is limited, adipose depots cannot produce new cells, and instead excessive fatty acids must be stored in larger fat cells (hypertrophy), in other organs such as liver and muscle and in the vasculature – leading to increased risk of heart disease and Type II Diabetes.
In the UK currently ~50% of mothers are overweight or obese when entering pregnancy. Both epidemiological and animal model studies have shown that maternal obesity is a major risk factor for offspring metabolic disease. However, molecular mechanisms linking early life exposure to adult metabolic dysfunction, including compromised adipose expansion, are poorly understood.
We hypothesise that early life exposure to obesity prevents self-renewal and maintenance of the APC pool. This project will utilise a combination of data from mouse models and human genetics to identify molecular pathways that can be targeted therapeutically to maintain healthy adipose tissue for a lifetime.
In this project the student will use a combination of laboratory and computational techniques to:
1) Discover new gene regulatory networks associated with the APC expansion in response to maternal diet (RNAseq analysis, mouse early life physiology, Flow Cytometry). Year 1&2.
2) Determine if epigenetic pathways drive differences between dietary groups (Computational analysis, ATAC-seq) Year 2.
3) Explore human variation in genes/regulatory elements from candidate pathways using Genomics England resources (computational analyses with ‘big data’) Years 1-3.
4) Test gene editing/epigenetic editing approaches to modify adipose progenitor behaviour (CrispR targeting, ex-vivo cell culture) Years 2-3.

Representative Publications

Constitutive Activation of β-Catenin in Conventional Dendritic Cells Increases the Insulin Reserve to Ameliorate the Development of Type 2 Diabetes in Mice. Macdougall CE, Wood EG, Solomou A, Scagliotti V, Taketo MM, Gaston-Massuet C, Marelli-Berg FM, Charalambous M, Longhi MP. Diabetes. 2019 Jul;68(7):1473-1484. doi: 10.2337/db18-1243. Epub 2019 May 2. PMID: 31048369 • Visceral Adipose Tissue Immune Homeostasis Is Regulated by the Crosstalk between Adipocytes and Dendritic Cell Subsets. Macdougall CE, Wood EG, Loschko J, Scagliotti V, Cassidy FC, Robinson ME, Feldhahn N, Castellano L, Voisin MB, Marelli-Berg F, Gaston-Massuet C, Charalambous M, Longhi MP. Cell Metab. 2018 Mar 6;27(3):588-601.e4. doi: 10.1016/j.cmet.2018.02.007. PMID: 29514067 • DLK1/PREF1 regulates nutrient metabolism and protects from steatosis. Charalambous M, Da Rocha ST, Radford EJ, Medina-Gomez G, Curran S, Pinnock SB, Ferrón SR, Vidal-Puig A, Ferguson-Smith AC. Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):16088-93. doi: 10.1073/pnas.1406119111. Epub 2014 Oct 27. PMID: 25349437
Prickett, A.R., Ishida, M, B√∂hm, S., Frost, J.M., Puszyk, W., Abu-Amero S., Stanier P., Schulz R., Moore G.E. and Oakey R.J. Genome wide methylation analysis in Silver Russell syndrome, Human Genetics, 2015 Mar;134(3):317-32. PMID:25563730. • Contreras-Castillo, S., Montibus, B., Rocha, A., Duke, W., von Meyenn, F. McLornan, D., Harrison, C., Mullally, A., Schulz, R., Oakey, R.J. Hydroxycarbamide effect on DNA methylation and gene expression in myeloproliferative neoplasms. Genome Research, 2021Aug, 31:1381-1394. PMID: 34244229 • Wilson, B.C., Boehme, L., Annibali, A., Hodgkinson, A., Carroll, T.S., Oakey, R.J. and Seitan, V.C. Intellectual disability-associated factor Zbtb11 cooperates with NRF-2/GABP to control mitochondrial function. Nature Communications. 2020 Oct 29;11(1):5469. doi: 10.1038/s41467-020-19205-x. PMID: 33122634.