How do our cells, all of which have exactly the same set of genes, adopt such different fates, morphologies and functions? How do cells then respond to the environmental cues around them in order to make up a living, growing, healthy organism? The answer to the first question lies in the fact that our genome is subject to epigenetic regulation, which ensures its stability and determines when and where genes are expressed to produce their transcript and protein products. And the answer to the second question lies largely within the fact that these proteins, which then go on to execute most of the cell’s functions, are themselves subject to regulatory mechanisms, which are initiated by environmental cues and determine when, where and how a protein will function. Our lab combines these two fascinating biological questions to understand how the genome regulators are themselves regulated during early development of the mammalian embryo (Christophorou et al, Nature, 2014; Hay et al., In preparation).
DNA methylation, the prototypical epigenetic modification, undergoes dramatic reprogramming (erasure and re-establishment) during this developmental time. While the molecules that regulate DNA methylation are well understood, the molecular mechanisms that modulate their function remain ill-defined. Using a series of biochemical and proteomic experiments, we have identified proteins that bind DNA methylation regulators. These protein-protein interactions happen differentially in cellular contexts of DNA methylation erasure and re-establishment. Our preliminary data show that perturbing some of these proteins affects the rate and extend of methylation reprogramming, making them good candidates in our quest to discover novel mechanisms of epigenetic regulation in development. Notably, some of these proteins are known to be associated with neurodevelopmental disorders such as autism and misregulation of DNA methylation has a well-established role in the development of such disorders.
The specific aims of this project are:
1. To test the hypothesis that our candidate proteins modulate the ability of the DNA methyltransferase machinery to deposit DNA methylation in early development
2. To understand the precise molecular mechanisms through which the candidate factors modulate DNA methylation
3. To assess whether perturbation of the candidate factors impacts the development and function of stem cells and neural progenitor cells
The student will obtain training in protein biochemistry, molecular biology and cell biology. They will utilize genome editing, proteomic and genomic methodologies and assays of cellular differentiation and reprogramming to address the above questions. Importantly, they will be trained in experimental design, critical thinking and data interpretation and presentation.
Possible out comes of this project are:
- Identification of new factors that regulate the epigenome
- Identification of novel molecular mechanisms of regulating stem and neural progenitor cell function
- A better understanding of the cell signaling pathways that modulate cell fate
Findings of this work may have far-reaching implications in biomedicine: identifying the mechanisms and factors that regulate DNA methylation in development would make it possible to address whether neurodevelopmental disorders are reversible through modulation of these factors. In addition, it would make it possible to design pharmacological interventions for diseases, such as developmental syndromes and cancer, and for disabilities, such as autism.
epigenetics, stem cells, cell signaling, DNA methylation, development
Lab website: http://www.ed.ac.uk/mrc-human-genetics-unit/research/christophorou-group
PhD Student Opportunities 2020
The Babraham Institute is a world-leader in fundamental biological research investigating the systems that underpin development and healthy ageing. It is a recognised postgraduate University Partner Institute of the University of Cambridge. Starting October 2020 a number of Studentships will be available leading to a University of Cambridge PhD degree. These studentships can be awarded for up to 3.5 or 4 years. In addition, studentships funded by a range of University of Cambridge funding schemes can be held at the Babraham Institute (see the student pages of our website here - https://www.babraham.ac.uk/vacancies-training/phd-programme
) and for specific funding sources for EU and overseas graduate student at Cambridge, please visit here - http://www.graduate.study.cam.ac.uk/finance/funding
Please see our website (http://www.babraham.ac.uk/
) and the BBSRC website (https://bbsrc.ukri.org/skills/
) for details of eligibility and funding. Non-EU nationals must find funding for academic fees and personal support. In cases where applicants must find their own funding, we will require evidence that the level of funding is at least equal to the standard BBSRC/MRC PhD funding package.
Students will join a thriving scientific community situated on an attractive parkland campus near Cambridge. Our 60 students are all members of Cambridge Colleges and participate fully in University social and academic life - https://www.gradschl.lifesci.cam.ac.uk/
Details of our interactive scientific programmes can be found on the Babraham Institute website - http://www.babraham.ac.uk/
As a student at the Institute, you will have access to all of our outstanding science facilities (https://www.babraham.ac.uk/science-services
), each one providing specialist equipment and expertise to support key research techniques and technologies. In addition to our animal facility, imaging, chemical synthesis and mass spectrometry we are able to offer transgenics services, flow cytometry, lipidomics, next-generation sequencing and a highly specialist team of bioinformaticians. In addition, several of our facilities operate training programmes to help you develop your own skills in these key research areas. The Institute’s research groups also incorporate a selection of other cutting-edge specialties including single-cell and multiomics approaches.
All applications for PhD Studentships at the Babraham Institute need to be made using the University of Cambridge Graduate Application Portal regardless of funding source: https://www.graduate.study.cam.ac.uk/
Please see the “Applying for a PhD” pages on our website for further details of the application process: https://www.babraham.ac.uk/vacancies-training/phd-programme/phd-applications
Short-listed applicants will be invited to attend our Institute Graduate Open Day on Wednesday 22nd January 2020 for a series of interviews. This will give applicants an opportunity to meet Group Leaders and their research groups, as well as receiving a tour of our research facilities. Reasonable travel expenses will be paid to those invited.
Students will not be able to take up an award unless they meet all University eligibility criteria and are successful in securing admission to the University. In addition, they will not be able to apply for a visa (if needed) until they hold an unconditional offer from the University.
The deadline for submission of applications via the Graduate Application Portal is 3rd December 2019. Incomplete applications will not be considered.
If you would like more information, or have any questions not answered on our website or the University of Cambridge Graduate Admission site, please contact us:
Graduate Studies Assistant, Babraham Institute, Babraham Research Campus, CB22 3AT or email to [email protected]
An Equal opportunities employer. An Institute supported by the Biotechnology and Biological Sciences Research Council http://www.babraham.ac.uk