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Epigenetic control of stem cell potential during ageing

Principal Supervisor: Dr Leda Mirbahai - School of Biosciences

Co-supervisor: Warwick Dunn, Peter Laird, KwangHo Lee, Xiaojing Yang

PhD project title: Epigenetic control of stem cell potential during ageing

University of Registration: University of Birmingham

Project outline:

Adult stem cells are responsible for the homeostasis of each tissue type by giving rise to progenitor cells, which can subsequently differentiate into the mature cell types required for normal tissue function. However during ageing a decline in function and differentiation potential of stem cells have been observed. This has been partly contributed to age-dependent abnormality in the normal epigenome of stem cells, a concept referred to as epigenetic drift. Unlike terminally differentiated cells, the impact of epigenetic dysregulation in stem cells can become widespread as it can be transmitted to differentiated cells as well as being perpetuated and amplified within the stem cell population through self-renewal divisions. Furthermore, epigenetic abnormalities in the aged stem and progenitor cells can cause focal proliferative defects, an increased risk of development of tumours. The primary objectives of the project are 1) to comprehensively characterize abnormal DNA methylation changes accumulated in intestinal stem cells (ISCs) during ageing and 2) to investigate their impact on the ISC function and on intestinal tumorigenesis. We will apply fluorescence-activated cell soring, whole genome bisulfite sequencing, and genome editing methodologies for the isolation, genome-wide epigenetic profiling, and functional characterization of ISCs. In addition, we will employ transcriptome and metabolomics analyses to investigate the mechanisms and pathways that lead to such changes. We will use mouse and Daphnia as model systems as well as The Cancer Genome Atlas (TCGA) database to address different questions related to the project.

Training: Training will be provided in a range of cell molecular techniques, including adult stem cell isolation, as well as providing the opportunity to gain experience in the use of cutting edge (WGBS, RNA-seq and non-targeted mass spectrometry) techniques to analyse changes in the epigenome and metabolome with age. Furthermore, during this project the candidate will work with two model organism, Daphnia and mice. The project would suit a candidate who has an interest in understanding the biology that underpins stem cell function as well as the key molecular processes (e.g. DNA methylation) underpinning ageing.

Furthermore, the successful candidate will be spending equal time between the laboratories of the Professor Peter Laird at Van Andel Research Institute, MI, USA and Dr Leda Mirbahai and Dr Warwick Dunn at the University of Birmingham, UK. Therefore the project is suitable for candidates with an interest in working at a leading American research institute as well as University of Birmingham.

Candidate, funding and deadline: We seek an exceptional candidate with an undergraduate (distinction) or Master’s degree (can be pending) in the fields of molecular biology, biology and or epigenetics. Fully funded PhD project open to UK and EU citizens. To apply complete the online application form as well as the MIBTP form. Please highlight major achievements, prizes, internships, previous experience of using bioinformatics tools as well as contribution to scientific papers. The applicants are strongly encourages to contact Leda Mirbahai l dot mirbahai at bham dot ac dot uk with a copy of their CV and cover letter prior to completing the online application.

References: 

  1. Sun et al., (2014) Epigenomic profiling of young and aged HSCs reveals concerted changes during ageing that reinforce self-renewal. Cell Stem Cell. 14 (5): 673-688.
  2. Teschendorff et al., (2013) Age-associated epigenetic drift: implications, and a case of epigenetic thrift? 22 (R1): R7-R15.
  3. Sheaffer et al., (2014) DNA methylation is required for the control of stem cell differentiation in the small intestine. Genes & Development. 28(6): 652–664.
  4. Widschwendter et al., (2007) Epigenetic stem cell signature in cancer. Nature Genetics. 9(2):157-8

BBSRC Strategic Research Priority: Molecules, cells and systems

Techniques that will be undertaken during the project:

  • Stem cell characterisation (staining, labelling and sorting using FACS)
  • Culturing Daphnia and working with mice
  • Confocal microscopy
  • Standard molecular techniques (e.g. DNA, RNA and metabolite extraction, PCR)
  • Standard epigenetic assays
  • CRISPR-Cas-mediated genome editing
  • Library preparation for HTS and analysis of HTS datasets

Contact: Dr Leda Mirbahai, University of Birmingham