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. 2014 Feb;9(2):276-85.
doi: 10.4161/epi.27021. Epub 2013 Nov 8.

Epigenomic elements enriched in the promoters of autoimmunity susceptibility genes

Mikhail G Dozmorov  1 , Jonathan D Wren  2 , Marta E Alarcón-Riquelme  3
Affiliations

Epigenomic elements enriched in the promoters of autoimmunity susceptibility genes

Mikhail G Dozmorov et al. Epigenetics. 2014 Feb.

Abstract

Genome-wide association studies have identified a number of autoimmune disease-susceptibility genes. Whether or not these loci share any regulatory or functional elements, however, is an open question. Finding such common regulators is of considerable research interest in order to define systemic therapeutic targets. The growing amount of experimental genomic annotations, particularly those from the ENCODE project, provide a wealth of opportunities to search for such commonalities. We hypothesized that regulatory commonalities might not only delineate a regulatory landscape predisposing to autoimmune diseases, but also define functional elements distinguishing specific diseases. We further investigated if, and how, disease-specific epigenomic elements can identify novel genes yet to be associated with the diseases. We evaluated transcription factors, histone modifications, and chromatin state data obtained from the ENCODE project for statistically significant over- or under-representation in the promoters of genes associated with Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), and Systemic Sclerosis (SSc). We identified BATF, BCL11A, IRF4, NFkB, PAX5, and PU.1 as transcription factors over-represented in SLE- and RA-susceptibility gene promoters. H3K4me1 and H3K4me2 epigenomic marks were associated with SLE susceptibility genes, and H3K9me3 was common to both SLE and RA. In contrast to a transcriptionally active signature in SLE and RA, SSc-susceptibility genes were depleted in activating epigenomic elements. Using epigenomic elements enriched in SLE and RA, we identified additional immune and B cell signaling-related genes with the same elements in their promoters. Our analysis suggests common and disease-specific epigenomic elements that may define novel therapeutic targets for controlling aberrant activation of autoimmune susceptibility genes.

Keywords: ENCODE; GenomeRunner; autoimmunity; epigenetics; genome.

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Figures

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Figure 1. Schematic diagram of the analysis strategy. Disease-associated gene sets were obtained from GWAS reviews, and genomic coordinates of the promoters were extracted. They were tested for the enrichment in TFBSs, histone marks, chromatin segmentation states using GenomeRunner method. Disease-specific sets of epigenomic elements were identified. Additional disease-associated genes were prioritized by the presence of disease-specific epigenomic elements.
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Figure 2. Enrichment of 7 transcription factor binding sites in the promoters of SLE- and RA-associated gene sets and depletion of 6 TFBSs in the promoters of SSc-associated gene set. Out of 148 TFBSs obtained with ChIP-seq by the ENCODE project, only TFBSs enriched/depleted in the promoters of autoimmune-related gene sets, and their co-localization tendency are shown. (A) Enrichment/depletion analysis in the promoters of autoimmune-associated gene sets. (B) Co-localization tendency among enriched TFBSs.
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Figure 3. “Strong enhancer” chromatin state, H3K9me3, H3K4me1, H3K4me2, and H3K79me2 histone modification marks are enriched in the promoters of SLE- and RA-associated gene sets. In contrast, “heterochromatin” state was depleted. Chromatin segmentation states (A) and histone modification marks (B) from Gm12878 cell line enriched in the promoters of autoimmune-associated gene sets
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