Abstract
BackgroundSystemic lupus erythematosus (SLE) is a multi-system, complex disease in which the environment interacts with inherited genes to produce broad phenotypes with inter-individual variability. Of 46 single nucleotide polymorphisms (SNPs) shown to confer genetic risk for SLE in recent genome-wide association studies, 30 lie within noncoding regions of the human genome. We therefore sought to identify and describe the functional elements (aside from genes) located within these regions of interest.MethodsWe used chromatin immunoprecipitation followed by sequencing to identify epigenetic marks associated with enhancer function in adult neutrophils to determine whether enhancer-associated histone marks were enriched within the linkage disequilibrium (LD) blocks encompassing the 46 SNPs of interest. We also interrogated available data in Roadmap Epigenomics for CD4+ T cells and CD19+ B cells to identify these same elements in lymphoid cells.ResultsAll three cell types demonstrated enrichment of enhancer-associated histone marks compared with genomic background within LD blocks encoded by SLE-associated SNPs. In addition, within the promoter regions of these LD blocks, all three cell types demonstrated enrichment for transcription factor binding sites above genomic background. In CD19+ B cells, all but one of the LD blocks of interest were also enriched for enhancer-associated histone marks.ConclusionsMuch of the genetic risk for SLE lies within or near genomic regions of disease-relevant cells that are enriched for epigenetic marks associated with enhancer function. Elucidating the specific roles of these noncoding elements within these cell-type-specific genomes will be crucial to our understanding of SLE pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1169-9) contains supplementary material, which is available to authorized users.
Highlights
Systemic lupus erythematosus (SLE) is a multi-system, complex disease in which the environment interacts with inherited genes to produce broad phenotypes with inter-individual variability
We demonstrate that these SLE-associated Single nucleotide polymorphism (SNP) lie within linkage disequilibrium (LD) blocks containing histone marks commonly associated with enhancer function
We identified these marks in three cell types known to contribute to SLE pathogenesis and/or disease manifestations: CD4+ T cells, CD19+ B cells, and neutrophils
Summary
We used chromatin immunoprecipitation followed by sequencing to identify epigenetic marks associated with enhancer function in adult neutrophils to determine whether enhancer-associated histone marks were enriched within the linkage disequilibrium (LD) blocks encompassing the 46 SNPs of interest. We interrogated available data in Roadmap Epigenomics for CD4+ T cells and CD19+ B cells to identify these same elements in lymphoid cells. CD19+ B-cell and CD4+ T-cell data were queried from ENCODE, while neutrophil RNA sequencing (RNAseq) and chromatin immunoprecipitation sequencing (ChIP-seq) data for H3K4me1/H3K27ac data were generated in our laboratory and have been reported recently [11]. Laboratory methods for ChIP-seq and RNAseq data are described briefly in the following. Because neutrophils were not among the cells studied in either the ENCODE or Roadmap Epigenomics projects, we sought to create a genomic map for enhancer element locations using normal adult neutrophils. We obtained neutrophils from three healthy adults aged 25–40 using techniques we have described previously [11]
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