Babraham Institute and Sanger scientists find ‘dark matter’ switch is key to inflammatory diseases
What is it that makes some people susceptible to autoimmune and allergic conditions such as Crohn’s, type I diabetes, asthma and inflammatory bowel disease?
A study led by researchers at the Babraham Institute, in collaboration with the Wellcome Sanger Institute, suggests the answer may lie in ‘dark matter’ regions of the human genome that do not encode proteins.
A key genetic switch has been found that helps keep immune responses in check - and the research has identified a new potential therapeutic target for the treatment of inflammatory diseases.
Known as an enhancer element, this switch is required by the immune system’s peace-keepers - regulatory T cells, or Tregs - to balance its responses.
Dr Rahul Roychoudhuri, lead researcher and Babraham Institute group leader, said: “The immune system needs a way of preventing reactions to harmless self and foreign substances and Treg cells play a vital role in this.
“They’re also crucial in maintaining balance in the immune system, so that our immune responses are kept in check during infections.
“Tregs only represent a small percentage of the cells making up our complete immune system but they’re essential; without them we die from excessive inflammation.
“Despite this important role, there has been little evidence that unequivocally links the genetic variations that cause certain individuals to be susceptible to inflammatory diseases to changes in Treg function.
“It turns out that non-protein coding regions provided us with the opportunity to address this important question in the field.”
The study, published in the journal Nature, was carried out in mice and human cells and involving collaborations with research institutions in the UK and worldwide.
Scientists have, over the last 20 years, narrowed down the genetic basis of susceptibility to complex autoimmune and allergic diseases like Crohn’s disease, ulcerative colitis, type 1 diabetes and asthma, to a particular region of chromosome 11.
Through large-scale genome-wide association studies (GWAS) - which are likened to spot-the-difference comparisons between the genomes of individuals with and without a disease - the researchers were able to highlight regions of variation in the DNA code, identifying potential genetic causes and possible drug targets.
Many of the variations are concentrated within non-protein coding areas, meaning there is not always a clear gene target to use for developing new treatments.
Advances in sequencing-based approaches have demonstrated such disease-associated genetic changes are concentrated within regions of DNA called enhancers - switches that precisely regulate the expression of genes.
Scientists are now able to map physical interactions between different remote parts of the genome in 3D, meaning they can connect enhancers in non-coding regions with their target gene.
These methods were used by the research team to study the role of this dark matter in immune disease risk, along with the phenomenon known as shared synteny.
This describes how sometimes it is not just genes that are conserved - that is, the same - between species, but a whole section of the genome.
It has been described as like finding part of your book collection duplicated in your neighbour’s house - including the order they are arranged on the shelf.
Translating what they knew about the enhancer in the human genome, the researchers were therefore able to find the corresponding region in mice, and explore the biological impact of removing it in mouse models.
The enhancer element, they learned, controls the expression of a gene in Treg cells that encodes a protein called GARP (Glycoprotein A Repetitions Predominant).
Deleting this enhancer element caused the loss of the GARP protein in Treg cells, leading to an uncontrolled response that triggered inflammation of the colon lining.
This proved the enhancer is required for the Treg-mediated suppression of colitis, using this GARP protein.
They demonstrated a similar effect in human Treg cells from healthy blood donors.
The enhancer interacted with the human form of the same gene and genomic variations in the enhancer element were associated with reduced GARP expression.
Dr Gosia Trynka, a senior author on the paper from the Wellcome Sanger Institute and Open Targets, said: “Genetic variation provides important clues into disease processes that can be targeted by drugs.
“In our joint efforts here, we combined human and mouse research to gain invaluable insight into complex processes underlying immune diseases.
“This has identified GARP as a promising new drug target and brings us a step closer to developing more efficient therapies for people suffering from diseases such as asthma or inflammatory bowel disease.”
Dr Roychoudhuri added: “Decades of research have now identified the variations in our genomes that make some of us more susceptible to inflammatory diseases than others.
“It has been very difficult, however, to make sense of how these variations relate to immune disease since many of them occur in non-protein-coding regions, and therefore the implications of these changes are poorly understood.
“Studies such as these will enable us to link the genetic switches that commonly reside in such disease-associated non-coding regions with the genes they control in different cell types. This will yield new insights into the cell types and genes underlying disease biology and provide new targets for therapeutic development.”
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