Unmasking disease risk hidden in haematopoietic enhancers

Abstract

Histones are subject to a wide range of modifications, which are differentially regulated across cell types to modulate gene expression. The simultaneous presence of different sets of histone modifications in a genomic location is correlated with the function of the DNA wrapped around such histones. This information is especially relevant to understanding the role of non-coding regions of the genome, such as enhancers, which modulate the expression of target genes in specific conditions and a cell type-specific manner. Questions have been raised about the potential role of enhancers in the modulation of genes involved in complex immune-mediated diseases because most genetic variants associated with such diseases lie in non-coding regions. However, the exact localisation of enhancers in haematopoietic cell types is unclear. Different groups of researchers have made inconsistent efforts to annotate the epigenome of focused subgroups of cell types, making the comparison among genomic locations of enhancers across multiple haematopoietic cell types unfeasible. I produced the most complete collection of epigenomic annotations of haematopoietic cell types based on the presence of six different histone modifications across the epigenome of 107 samples from 31 different cell types of healthy individuals. I also identified around 200 diseases with associated non-coding genetic variants colocalising regions annotated as enhancers in different subsets of haematopoietic cell types, thus providing an invaluable resource for the interpretation of non-coding variants associated with complex diseases. I used Inflammatory Bowel disease and cardiovascular disease as examples to showcase our dataset's leverage for identifying complex diseases causing genes.