Grant: Operating Grant

In living cells, DNA exists in a packaged form: it is wrapped in proteins. Depending on the packaging, DNA is either easily accessible for transcription factors (proteins that help reading the information stored in DNA) and actively functioning, or is not accessible and is silent. DNA packaging is also termed "epigenetic state". An abnormal epigenetic state may silence an important gene, and thereby cause disease. We will test the role of epigenetic states in predisposition to asthma. Asthma is an autoimmune disorder that affects about 300 million people worldwide, a large proportion of whom are children. It has a strong hereditary component and is thought to result from interaction between genes and environment. During the last 20 years, asthma has been on the rise with a steeper increase in children. This is attributed to environmental factors, such as allergens and pollution. Genetic studies found that the DNA sequence in a region of chromosome 17 increases the risk of developing asthma. However, the exact mechanism underlying the relationship between DNA sequence change and risk to develop asthma remains unclear. Our work shows that epigenetic states are being also affected in this region. We hypothesize that changes in the DNA sequence of this specific region of human chromosome 17 provoke changes in DNA packaging that in turn lead to abnormal functioning of neighboring genes and cause predisposition to asthma. To test this hypothesis we will study gene regulation in the asthma-associated region of human chromosome 17. This work will help to better understand how common genetic variants lead to disease susceptibility in humans; clarify the pathogenesis of autoimmune disease, including asthma; and eventually help the treatment and management of autoimmune disorders.