A photo of Iouri Chepelev.
Principal Investigator: Iouri Cheplevev, PhD

Human major histocompatibility complex (MHC) is a genomic region on chromosome 6 of approximately 1/1000th the size of the human genome that encodes numerous genes with important roles in the regulation of the immune system and other fundamental cellular processes. This locus has been associated with more than 100 different diseases. The MHC represents the strongest susceptibility locus for autoimmune diseases. To better understand how genes interact to provoke lupus, we will apply cutting-edge technology to map the three- dimensional structure of MHC region in immune cells from lupus patients.

The DNA in our cells is often depicted as a loose strand containing thousands of genes in a predictable linear sequence. But in reality, our two-meters long DNA is tightly packaged like a tangled ball of yarn inside a tiny cell nucleus. The positioning of genes inside the ball profoundly affects how they function and interact with each other. Our research will zoom in on lupus-associated genes in the three-dimensional, tangled ball of DNA in the MHC region. 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 the diagnosis of lupus.

Given the central importance of MHC in many diseases, our findings will have far-reaching implications beyond the single disease we focus on in this pilot study. The combination of novel high-throughput methods used in this project will become a prototype for mapping disease-causal genetic variants in the MHC region and elucidating mechanisms of gene dysregulation in other pediatric diseases of high relevance to Cincinnati Children’s mission.