Inappropriate use of control switches in the genome may weaken our body’s defences against illness and could contribute to leukaemia, according to a new study published today (17th November) in Frontiers in Immunology. The research, led by Dr Anne Corcoran from the Babraham Institute in Cambridge, examines how the immune system makes antibodies, proteins that help to fight infections.
The immune system can fight almost any infection by creating customised antibodies. Each antibody is made by combining a few genes from a large selection of possible components in an process called V(D)J recombination. Like building blocks, each combination of genes creates a unique antibody. Some of these genetic building blocks are much more likely to be used by the immune system than others, and it is not clear why. This new study uses mice to identify for the first time a set of epigenetic marks and proteins, which behave like genetic switches and that together control which genes contribute to making antibodies.
The best antibodies are very precise in locking on to the causes of a particular illness. By combining genes in many different ways to make different antibodies, the immune system creates antibodies with the precision needed to identify and fight any possible infection. Some people have genetic conditions that mean their immune system can not produce a large enough variety of antibodies, so they are less able to fight diseases. The immune system also weakens as we age. In both cases, changes to this newly discovered control mechanism could be partly responsible for these weaknesses.
First author on the paper and postdoctoral researcher at the Babraham Institute, Dr Louise Matheson, said: “Our bodies are able to produce millions of different antibodies from just a few genes using V(D)J recombination, so it’s an incredibly complex system. We wanted to understand how this process is controlled as well as which epigenetic marks and proteins are involved. By understanding these systems we can learn how to better control the immune system and how to help it fight infections.”
Antibodies are made using several clusters of genes, called loci. This study focuses on just one locus in mice, known as immunoglobulin kappa. In mice and humans, the kappa locus contains around 140 genes for making parts of an antibody. By using a new method called VDJ-seq, a type of DNA sequencing, the researchers showed that the most commonly used antibody genes are labelled with specific histone methylations, a type of epigenetic mark. The team also found a link between the most active genes and two proteins called PU.1 and IKAROS.
The scientist that led the research, Dr Anne Corcoran, Group Leader at the Babraham Institute, said: “We have discovered some of the key factors that switch on the genes that make antibodies. This is a valuable insight into how the immune system protects our bodies, and what may be at fault when the immune system is weakened. This will ultimately help us to design diagnostic tests for people affected by recurrent infections and to devise therapies to boost the body’s response to infection.”
The team suggest that loss of the epigenetic marks and proteins highlighted by their study could contribute to weakening of the immune system in old age and in some genetic conditions. If their future research can prove this, then it could lead to new treatments to strengthen the immune system and help more of us to stay healthy for longer into old age.
Matheson, L.S., Bolland, D.J., Chovanec, P., Krueger, F., Andrews, S., Koohy, H., Corcoran, A.E., Local chromatin features including PU.1 and IKAROS binding and H3K4 methylation shape the repertoire of immunoglobulin kappa genes chosen for V(D)J recombination, Frontiers in Immunology, 2017.
This research was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) through an Institute Strategic Programme Grant for Nuclear Dynamics.
Dr Jonathan Lawson, Babraham Institute Communications Manager email@example.com
ShutterStock. Image of an antibody.
Affiliated Authors (in author order):
Louise Matheson, Daniel Bolland, Peter Chovanec, Hashem Koohy – Nuclear Dynamics Programme, Babraham Institute
Dr Anne Corcoran – Group Leader, Immunology Programme, Babraham Institute
Felix Krueger, Simon Andrews – Bioinformatics Group, Babraham Institute
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. Animals are only used in Babraham Institute research when their use is essential to address a specific scientific goal, which cannot be studied through other means. The main species used are laboratory strains of rodents, with limited numbers of other species. We do not house cats, dogs, horses or primates at the Babraham Research Campus for research purposes.
The use of animals in this study was performed in accordance with UK Home Office rules and ARRIVE guidelines with all protocols approved by the Babraham Institute Animal Welfare and Ethical Review Body (AWERB) and performed under Home Office Project Licence 80/2529. The study used male and female mice: C57BL/6 wild type mice and Rag1-/-/VH81X transgenic mice. Mice were housed in groups of up to five in the Biological Support Unit at the Babraham Institute under specific pathogen-free conditions.
Multiple independent experiments were carried out using several biological replicates. In accordance with the 3Rs, we used the minimum number of mice necessary to collect sufficient cells per experiment (15 C57BL/6 wild-type mice; nine Rag1-/-/VH81X transgenic mice).
Mice were checked daily by qualified technicians and were healthy and active throughout the study. Environment enrichment was provided (e.g. tunnels, elevated rafts) as well as food treats and nesting material. Tissue samples were collected from mice between the ages of 6 and 12 weeks.
Importantly, for large parts of the study, alternatives to animal models including publically available next generation sequencing datasets and computational models were used.
Please follow the link for further details of the Institute’s animal research and our animal welfare practices: http://www.babraham.ac.uk/about-us/animal-research
About the Babraham Institute:
The Babraham Institute receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC) to undertake world-class life sciences research. Its goal is to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Research focuses on signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing.
17 November 2017