Epigenetic and signalling mechanisms underpinning impaired lymphocyte development and antibody recombination in ageing
Lead Research Organisation:
University of Cambridge
Department Name: Graduate School of Life Sciences
Abstract
This project will take a top-down and a bottom-up approach. First we will investigate the consequences of loss of these components in established mouse models in which the relevant genes are deleted specifically in bone marrow B cells. We will ask: How does deletion impact on B cell developmental progression, proliferation, recombination, diversity of the antibody repertoire? How are downstream signaling pathways altered and how does this in turn affect the transcriptome and its epigenetic drivers?
Second, we will investigate how these components are regulated at the epigenetic level. Our findings suggest that they are repressed by Polycomb-mediated and miRNA mechanisms, and by loss of contact with distal enhancers. We will investigate these mechanisms using Crispr-Cas9 targetting of key DNA elements and appropriate inhibitors in in vitro B cell systems, to determine the key epigenetic regulators impaired in ageing.
The PhD project will include both experimental ('wet') and bioinformatics ('dry) components. Techniques are all well-established in the lab and will include flow cytometry, mouse models, signaling assays, RNA-seq, VDJ-seq, capture HiC, ChIP-seq, single cell sequencing, bioinformatics, Crispr-Cas knockout. Extensive training and assistance in bioinformatics will be provided by the Babraham Bioinformatics Group.
Second, we will investigate how these components are regulated at the epigenetic level. Our findings suggest that they are repressed by Polycomb-mediated and miRNA mechanisms, and by loss of contact with distal enhancers. We will investigate these mechanisms using Crispr-Cas9 targetting of key DNA elements and appropriate inhibitors in in vitro B cell systems, to determine the key epigenetic regulators impaired in ageing.
The PhD project will include both experimental ('wet') and bioinformatics ('dry) components. Techniques are all well-established in the lab and will include flow cytometry, mouse models, signaling assays, RNA-seq, VDJ-seq, capture HiC, ChIP-seq, single cell sequencing, bioinformatics, Crispr-Cas knockout. Extensive training and assistance in bioinformatics will be provided by the Babraham Bioinformatics Group.
Organisations
People |
ORCID iD |
Anne Corcoran (Primary Supervisor) | |
Elise French (Student) |