Individual histone modification roles in regulation of transcription and cell decision-making
We are looking for a highly-motivated, technically-able and independent-thinking candidate to undertake a PhD project exploring the role of individual histone modifications in nuclear organisation, regulation of transcription, and the process of stem cell fate decision in development, aging and disease. The project will be supervised by Dr Cristina Pina (https://www.brunel.ac.uk/people/cristina-pina) and Prof Joanna Bridger (https://www.brunel.ac.uk/people/joanna-bridger) at the Department of Life Sciences of Brunel University London (College of Health, Medicine and Life Sciences). Both groups are part of the Centre for Genome Engineering and Maintenance (https://www.brunel.ac.uk/research/Centres/Genome-Engineering-and-Maintenance), where Prof Bridger in Centre Director, and Dr Pina is the Cluster Lead for Cancer Mechanisms.
The Pina lab specialises in epigenetic and transcriptional regulation of normal, with an interest in mechanisms of leukaemia initiation and progression. We use single-cell technologies, genome-wide transcriptional and epigenetic profiling with next-generation sequencing, and genetic and epigenetic editing of individual loci with CRISPR-Cas9-based tools, to investigate in vitro and in vivo models of stem cell fate decisions. The Bridger lab has long-standing expertise in the role of nuclear organisation in cell decisions during normal and pathological aging , and uses state-of-the-art imaging techniques to understand nuclear dynamics and genome stability.
In recent years, the Pina lab unveiled a role for histone acetyl-transferase KAT2A/Kat2a in stabilising the frequency at which individual genes are transcribed . We suggested that loss of Kat2a allows normal and malignant stem cells to drift away from their self-renewing state to initiate differentiation programmes , resulting in diversification of cell types. Kat2a is responsible for acetylation of lysine 9 of Histone 3. It functions in 2 macromolecular complexes, SAGA and ATAC, which target distinct sets of genes and have additional histone modification activities, respectively H2AK120 and H2BK119 de-ubiquitination, and H4K5 acetylation. The relative contribution of the 2 complexes, and of their individual histone modifications, to the effects on transcription and cell fate, however, remain largely uncharacterised .
The successful candidate will specifically investigate the roles of H3K9ac and H4K5ac in the dynamics of locus activation and transcription and the consequences to stem cell differentiation systems. They will generate histone acetylation mutants or use Cas9-guided modification of candidate loci combined with single-molecule RNA-FISH to investigate the dynamic regulation of locus activity in mouse embryonic stem (mES) cells. Nuclear imaging will identify higher-order consequences to chromatin organisation. Modified mES cells will be studied in 2D and 3D self-renewal and differentiation systems to understand consequences to cell decision-making.
Candidates will have a First or Upper Second-class BSc (Hons) degree or equivalent in Biology, Biomedical Sciences, Natural Sciences, Life Sciences, Genetics, Biochemistry or similar areas, with significant lab experience. An MSc qualification is desirable but not essential. Candidates will be very competent lab workers who value attention to detail, enjoy technical challenges and successfully persevere. They will have excellent oral and written communication skills, and will demonstrate the capacity to autonomously research, synthesise and critically evaluate relevant literature. They will successfully work independently and as part of a team, and will demonstrate a dedicated and flexible approach to work.
Informal enquiries can be made to Cristina Pina (email@example.com) or Joanna Bridger (Joannafirstname.lastname@example.org). We look forward to hearing from you.
How to apply
If you are interested in applying for the above PhD topic please follow the steps below:
- Contact the supervisor by email or phone to discuss your interest and find out if you woold be suitable. Supervisor details can be found on this topic page. The supervisor will guide you in developing the topic-specific research proposal, which will form part of your application.
- Click on the 'Apply here' button on this page and you will be taken to the relevant PhD course page, where you can apply using an online application.
- Complete the online application indicating your selected supervisor and include the research proposal for the topic you have selected.
This is a self funded topic
Brunel offers a number of funding options to research students that help cover the cost of their tuition fees, contribute to living expenses or both. See more information here: https://www.brunel.ac.uk/research/Research-degrees/Research-degree-funding. The UK Government is also offering Doctoral Student Loans for eligible students, and there is some funding available through the Research Councils. Many of our international students benefit from funding provided by their governments or employers. Brunel alumni enjoy tuition fee discounts of 15%.
Meet the Supervisor(s)
Cristina Correia Antunes Pina
- I am a clinically-trained research scientist working in the field of cancer epigenetics. I am fascinated by the mechanisms through which cells diversify their molecular composition, and consequently vary their morphology and their function, to make organs, regenerate tissues, and produce tumours. While some of those diversification mechanisms rely on genetic mutations, others explore the way in which cells read their genes to produce the RNA and proteins that underlie cell function. The latter are referred to as epigenetic mechanisms.
My research is focused on understanding and manipulating epigenetic mechanisms to alter cell identity, and in particular, it aims to probe their role in cancer evolution in an attempt to unveil new therapies.
- I have been at Brunel University London since the start of this century. This is when I established my own independent laboratory - The Laboratory of Nuclear and Genomic Health. Our research concerns how the genome is spatially organised, influenced and manipulated within its environment, the cell nucleus. The group has had a number of major advances and is currently focused on aspects of genome behaviour in replicative senescence, the premature ageing disease Hutchinson-Gilford Progeria Syndrome, host:pathogen interactions and female cancers. We are wish to understand how structures such as the nuclear lamina, nucleoskeleton and nuclear motors influence the functionality of the genome.