Unwrapping the 3D genome to map autoimmune disease
This honours projects seeks to unravelling the chromatin interactome to map the genetic risk of type 1 diabetes.
Autoimmune diseases have a genetic risk: GWAS have identified more than 200 regions containing genetic variations linked to autoimmune disease risk but how these variations contribute to disease has remained elusive. Critically, more than 80% of the disease linked variations identified in genome wide studies are not located in the coding regions of genes.
Autoimmune diseases genetic risk affects CD4 T cell specific enhancers: Up to 60% of candidate autoimmune disease associated variants are localised to regulatory elements (enhancers) active in lymphoid cells. These variants may alter the expression of the genes normally controlled by enhancers in Treg and T conv cells Discovering the target genes controlled by these enhancers will therefore pin-point the critical pathways disrupted in Treg and Tconv cells in autoimmune disease.
It is now clear that enhancers acting over large distances are critical for controlling the cell-type- specific transcription of target genes. Up to 50% of enhancer regions, and do not interact with the nearest gene(s), but interact with promoters hundreds to thousands of kilobases away via DNA looping.
This project will use Chromatin Conformation Capture (3C, 4Cseq and Hi-C), reveal actual connectivity between regulatory elements containing genetic risk and their targets.
Study molecular immunology
My lab is interested in how a healthy immune system balances being ready to react by swiftly fighting off pathogens, while maintaining tolerance to harmless challenges such as commensal bacteria, food and normal self-tissues.
The cellular immune repertoire in humans is broad, but we are focused on a T cell subset that is shaped along with the immune system from birth.
These cells are known as regulatory T cells, and they are accepted as the policemen of the immune system.
There is increasing evidence that in a wide number of disease states including autoimmune diseases such as Type 1 diabetes and Multiple Sclerosis, these cells fail to regulate the immune system, and allow inappropriate destruction of tissues that are essential for life.
In order to understand how this breaks down in disease one must first understand what is the basis of a healthy Treg. To do this we are focused on human cells and we use a number of state of the art gene discovery tools such as RNAseq, ATACseq, ChIPseq and HiC to identify and then confirm the key genes in Treg function.
As Treg play a role in autoimmune disease, cancer and transplantation tolerance, our research findings have a wide clinical application. Our honours projects are from parts of this overall research program. We currently have multiple grants, which provides lab support for students.