Single Nucleotide Polymorphisms with Cis-Regulatory Effects on Long Non-Coding Transcripts in Human Primary Monocytes

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.

A Genome-Wide Study of Allele-Specific Expression in Colorectal Cancer

“…However, in recent years, lncRNAs were reported to be involved in gene regulation and other cellular processes ( Quinn and Chang, 2016 ). With an ASE analysis, Almlof et al (2014) found that 22.9% (258 out of 1122) of intergenic lncRNAs were regulated by cis -rSNP in human primary monocytes, which is comparable to our analysis. Though the number of lncRNAs exceeded the protein coding genes, because of a much lower expression ( Iyer et al, 2015 ), a higher sequencing depth and more sensitive detector is required to quantify ASE in lncRNAs more efficiently.…”

BaalChIP: Bayesian analysis of allele-specific transcription factor binding in cancer genomes

“…Some studies have analyzed tumor and normal samples without making any adjustments to the applied methodology, which risks identifying false positives where the detected ASE is mainly due to copy-number alterations [ 11 ]. Others have removed all sites overlapping copy-number variants [ 7 , 12 , 13 ], or used the genomic DNA (gDNA) allelic ratios (ARs) to correct for the observed allelic imbalances [ 14 , 15 ] or to remove SNPs with allelic imbalances detected in the control input DNA [ 2 ], which is feasible only when the coverage at any assayed heterozygous site is high (>20 × if a binomial test is to be applied to reach adequate statistical power [ 9 , 12 ]). Recently, Liu et al [ 16 ] developed cisASE, a likelihood-based method for detecting ASE.…”

Fine mapping of the uterine leiomyoma locus on 1q43 close to a lncRNA in the RGS7-FH interval

“…The possibility that the association signal upstream of the target lncRNA overlaps a regulatory region with cis effects on the lncRNA expression and the target cis mRNA cannot be excluded. Several examples of co-regulated lncRNA and protein-coding loci by the same cis -rSNP, the so-called enhancer RNA (eRNA), have been reported ( Almlof et al . 2014 ).…”