Integrative Data Analysis to Uncover Transcription Factors Involved in Gene Dysregulation of Nine Au

Naghavi, Nader Hosseini, Steven M. Kerfoot, and Parisa Shooshtari

Autoimmune and inflammatory diseases affect about 5% of people worldwide and happen when the immune system mistakenly attacks the body’s own tissues. There are over 80 autoimmune diseases, with some targeting specific organs (like Type 1 Diabetes, which affects the pancreas) and others affecting multiple parts of the body (like Lupus). To develop better treatments, it's important to identify genes that might increase the risk of developing these diseases. 

A challenge with autoimmune diseases is that many different systems within cells can be affected. While each individual issue may be small, together they can cause significant health problems. Most of the mutations involved impact cells of the immune system, particularly by changing how certain proteins, called transcription factors, control the activity of specific genes. Scientists use methods like DNase-I-seq and ATAC-seq to figure out which parts of a cell’s DNA are active, and some which are not. 

In our project, we used available DNA data to identify which transcription factors and biological pathways might be involved in autoimmune diseases. We focused on regions of DNA that are “open” and accessible, where mutations might prevent transcription factors from attaching as they should. We looked at nine different autoimmune diseases and examined data from 35 types of cells and tissues. For each mutation, we identified which transcription factors might be affected, and in which cells the resulting gene disruptions could occur, giving us a clearer picture of how these diseases develop. 

In this study, we were able to report on key mutations in areas of DNA that are important for gene regulation, and how they are likely to impact transcription factors binding which translates to various autoimmune disorders including multiple sclerosis, irritable bowel disease and juvenile idiopathic arthritis. These findings will ultimately help researchers develop treatments that target these changes, potentially improving outcomes for people with autoimmune diseases. 

Link to full text: https://doi.org/10.1101/2024.04.24.591013