2015 Genetics, Human Lupus Biology
2015 Identifying Specific Lupus Genes Using New 3D imaging
To better understand how genes interact to provoke lupus, we will for the first time apply cutting-edge technology to map the three-dimensional structure of a stretch of DNA that is strongly associated with lupus. With this map, we will be able to locate specific genes that make people susceptible to lupus, which could help identify those at risk for lupus and speed diagnosis.
The DNA in our cells is often depicted as a single loose strand containing thousands of genes in a predictable linear sequence. But in reality, our DNA is tightly packaged like a tangled ball of yarn. The positioning of genes inside the ball profoundly effect how they function and interact with each other. Several genes are associated with lupus and autoimmunity. Our research will zoom in on these lupus-associated genes in the three-dimensional, tangled ball of DNA. By locating and visualizing lupus-associated genes, we hope to pinpoint critical interactions between genes that make people susceptible to lupus. Knowing these genetic risk factors could improve diagnosis of lupus.
Scientific Abstract: Identification of lupus causal variants at 8p23.1 by mapping 3D genome
Majority of systemic lupus erythematosus (SLE)-associated single nucleotide polymorphisms (SNPs) are located in regions of genome that encode regulatory instructions for where and when gene products are produced in cells of human body. The SLE-associated SNPs identified in human genetic studies are correlated proxies for SLE-causal genetic variants that may be located tens of thousands of base pairs away on a chromosome. The identification of precise genomic locations of SLE-causal variants remains a critical challenge. Human genome is folded to form a dynamic 3-dimensional structure inside cell nucleus and the regulatory regions are thought to interact with genes via DNA looping mechanism. The 8p23.1 region on human chromosome 8 contains many SLE-associated genetic loci. We will map the 3-dimensional structure of 8p23.1 region to identify precise locations of lupus-causal genetic variants. The SLE-causal variants and their long-distance physical interactions with genes both inside and outside of the 8p23.1 region identified in the course of this project will result in a novel candidate list of SLE-susceptibility genes and will shed new light on gene-regulatory mechanisms involved in the SLE etiology.
Disruption of long-distance DNA looping in SLE.
(A) Enhancer-gene DNA looping interaction results in activation of the gene.
(B) A mutation in enhancer DNA disrupts the interaction and turns off the gene.