Interrogation and modulation of epigenetic mechanisms in ageing B cell development

Lead Research Organisation: University of Cambridge
Department Name: Veterinary Medicine

Abstract

Theme: Bioscience for Health

Impairment of B cell development is a major cause of frailty in the elderly. This includes reduced B cell numbers and reduced antibody repertoire diversity, which together result in poor response to infection and reduced vaccine efficacy, and enormous cost to the NHS. This project combines the expertise of Dr Anne Corcoran, and Dr David Tough at GSK to investigate how B lymphocyte development and function is regulated by histone modifications, and how alterations therein contribute to impaired B cell function in ageing. GSK is the world leader in design of inhibitors of histone modifying enzymes and epigenetic reader proteins, including BET domain Brd family, Jarid and JMJD, ezh2 and G9a, with widespread anti-cancer and anti-inflammatory applications. These inhibitors will identify the effects of altering chromatin and transcriptional regulation in B cells, and test the potential to restore function.

Aims
- Genome-wide - To identify alterations in histone modifications that may underpin altered gene expression in ageing, and to modulate these with GSK inhibitors.
- Immunoglobulin loci - To determine which components of the two chromatin states are dysregulated in ageing and to modulate these to restore Igh repertoire.

This project will contribute to the BBSRC Strategic Research Priority, Bioscience underpinning health. In particular it will address the strategic priority of Ageing Research: Lifelong health and wellbeing. It will also contribute to the Data driven biology strategic priority by generating large novel datasets that will drive new hypotheses.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011194/1 30/09/2015 29/09/2023
1889030 Studentship BB/M011194/1 30/09/2016 29/09/2020 Samuel Rees
 
Description I have developed on previous work conducted in the Corcoran lab which looked at B cell development in ageing. most notably, I have been able to look at the transcriptome of individual mice (rather than pooled samples), and also have been able to link, from the same individual mice, the repertoire diversity of Immunoglobulin Heavy chain loci recombination (contributing to the final antibody diversity). In doing so, I have been able to deconvolute to some extent the heterogeneity of ageing phenotypes, and connect different ageing phenotypes with changes in antibody diversity.
I have also developed an in-vitro culture system for differentiating progenitor B cells from mouse bone marrow cells, and have shown reduced ability of B cells from older mice to recombine and express the Immunoglobulin Heavy chain protein compared to young mice B cells in-vitro. I have used this in-vitro model to explore further the causes of this impaired differentiation with age. For example, through mixed cultures of both young and aged cells, I have determined if the age-related defects to differentiation are intrinsic to the cells or as a result of their extrinsic environment. I have also introduced small molecule inhibitors for targets of interest into these cultures to see if they can recapitulate/restore the differentiation capacity of cells in-vitro.
Finally, I have been able to generate some human data to compare to my mouse data with regards to transcriptomic variance and ability to differentiate in-vitro. These data's suggest a certain mechanism of action that could be taking effect in both mice and humans, and thus provides therapeutic scope to the research conducted under this award.
Exploitation Route The connections made between transcriptome and antibody repertoire diversity could identify processes by which older progenitor B cells have impaired abilities to generate more diverse antibody repertoires. These processes, such as gene targets or expression of epigenetic regulators, could be explored further academically to establish a better understanding of what actually drives efficient B cell development. Non-academically, these same findings could provide insight for druggable targets that could restore the ability of older progenitor B cells to recombine successfully and generate more diverse antibody repertoires. Paired with the in-vitro culture system developed as part of this project, it is possible that candidate drugs to enhance old cells could be screened on this platform.
Sectors Pharmaceuticals and Medical Biotechnology

 
Description A level student work experience 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact A sixth form Year 12 student interested in studying Biology at University did one week's work experience, learning techniques, doing experiments and listening to our PhD students talking about their careers. The student had a very positive impression of undergraduate and post-graduate biology.
Year(s) Of Engagement Activity 2019
 
Description Royal Society Summer Ageing Clock 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Carolyn Rogers, PhD student, Sam Rees, PhD student, Peter Chovanec, PhD student, helped out at the Race against the Ageing Clock exhibition at the Royal Society. Over 500 attendees, media coverage, increased understanding from public of ageing processes.
Year(s) Of Engagement Activity 2018
 
Description Sixth from student work experience 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Sam Rees, second year PhD student in the Corcoran lab, hosted a Sixth form student for a week, teaching him molecular and cell culture skills, explaining our research. The student has now applied to University to study Biological Sciences
Year(s) Of Engagement Activity 2018