Abstract
We applied genome-wide allele-specific expression analysis of monocytes from 188 samples. Monocytes were purified from white blood cells of healthy blood donors to detect cis-acting genetic variation that regulates the expression of long non-coding RNAs. We analysed 8929 regions harboring genes for potential long non-coding RNA that were retrieved from data from the ENCODE project. Of these regions, 60% were annotated as intergenic, which implies that they do not overlap with protein-coding genes. Focusing on the intergenic regions, and using stringent analysis of the allele-specific expression data, we detected robust cis-regulatory SNPs in 258 out of 489 informative intergenic regions included in the analysis. The cis-regulatory SNPs that were significantly associated with allele-specific expression of long non-coding RNAs were enriched to enhancer regions marked for active or bivalent, poised chromatin by histone modifications. Out of the lncRNA regions regulated by cis-acting regulatory SNPs, 20% (n = 52) were co-regulated with the closest protein coding gene. We compared the identified cis-regulatory SNPs with those in the catalog of SNPs identified by genome-wide association studies of human diseases and traits. This comparison identified 32 SNPs in loci from genome-wide association studies that displayed a strong association signal with allele-specific expression of non-coding RNAs in monocytes, with p-values ranging from 6.7×10−7 to 9.5×10−89. The identified cis-regulatory SNPs are associated with diseases of the immune system, like multiple sclerosis and rheumatoid arthritis.
Highlights
Determination of allele-specific gene expression (ASE) levels by quantitative genotyping of heterozygous SNPs on the RNA level [1], with genome-wide panels of SNPs [2,3] can be used as a guide for identifying cis-acting genetic variants that regulate gene expression
Allele-specific expression of Long non-coding RNAs (lncRNAs) regions We explored cis-regulation of 8929 genomic regions harboring lncRNA from the ENCODE project using allele-specific expression (ASE) analysis of 188 RNA samples from human primary monocytes
We found that the mean expression levels of the lncRNAs were 1.5-fold lower than the expression levels of exons (Figure 1), while the lncRNAs were expressed at a 1.5-fold and 5.5-fold higher level than intronic and inter protein coding gene regions, respectively
Summary
Determination of allele-specific gene expression (ASE) levels by quantitative genotyping of heterozygous SNPs on the RNA level [1], with genome-wide panels of SNPs [2,3] can be used as a guide for identifying cis-acting genetic variants that regulate gene expression. ASE analysis is more powerful for detecting cisregulated gene expression than the total expression levels of genes determined by regular eQTL analysis [4]. The power and precision of ASE analysis to detect cis-regulatory SNPs (cis-rSNPs) stems from the fact that the differential expression of the two alleles of a SNP are measured in the same environment and have been exposed to the same environmental conditions in the cells from which the RNA was extracted [4]. Genome-wide ASE analysis by SNP genotyping has been applied to map cis-regulation of protein coding genes associated with human diseases and traits in lymphoblastoid cell lines [2,5], osteoblasts [6], fibroblasts [5,7], T-cells [8], and monocytes [5]
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