"ChIP Seq RA CD"""" · Identification of regulator variants in Rheumatoid Arthritis and Crohn’s Disease

Rheumatoid Arthritis (RA) and Crohn’s disease (CD) are two common chronic autoimmune and complex diseases where individual susceptibility is determined by a combination of environmental and genetic factors. Almost all of the ~100 risk alleles discovered through recent genetic studies fall in non-coding region and have an elusive function. We hypothesize that risk alleles impact gene regulation by altering regulatory elements (e.g. enhancers) controlling the expression levels of genes within the same pathogenic pathway. The cell-specific variation in regulatory element (RE) activity can be identified by assaying histone modifications which correlate with chromatin states and DNA accessibility. Recently, assaying these histone modifications has become possible with ChiP seq methods, which applies high-throughput sequencing to identify genomic segments bound to antibodies to specific histone modifications. However to identify the REs impacted by risk loci, it is first necessary to determine the cells type (CT) affected by these risk loci; these cell types are not obvious in autoimmune diseases. Exploiting data on genome-wide histone marks in a library of immune-CT, we will develop a statistical method to identify the likely key pathogenic cells type by looking for immune-CTs specifically enriched in active REs containing risk loci. Subsequently, we will develop an approach to determine the cell specific REs impacted by risk loci and establish putative regulatory variant within of REs and associated with these complex disorders. I will develop this approach in my Outgoing Host Institute (Harvard Medical School) using RA as model, and will then apply it to CD in my Return Host Institute (University of Liege) where I pursue my research on the effect of regulatory risk alleles on the cell specific gene expression. This proposal will allow the discovery of new drug targets that can ultimately result in novel specific therapies for RA and CD patients.