Multiple genome-wide studies have identified associations between outcome of HIV infection and polymorphisms in/around the gene encoding the HIV co-receptor CCR5, but the functional basis for the strongest of these associations, rs1015164 A/G, is unknown. We found that rs1015164, located 34KB downstream of CCR5, marks variation in an ATF1 binding site that controls expression of the antisense long non-coding RNA CCR5AS. Knockdown or enhancement of CCR5AS expression resulted in a corresponding change in CCR5 expression on CD4+ T cells. CCR5AS interfered with interactions between the RNA-binding protein Raly and the CCR5 3’ untranslated region, protecting CCR5 mRNA from Raly-mediated degradation. Reduction in CCR5 expression through inhibition of CCR5AS diminished infection of CD4+ T cells with CCR5-tropic HIV in vitro. These data represent a rare determination of the functional importance of a genome-wide disease association where expression of a long non-coding RNA affects level of HIV infection and disease progression.
The clinical outcomes of infections are highly variable among individuals and are determined by complex host-pathogen interactions. Genome-wide association studies (GWAS) are powerful tools to unravel common genetic variations that are associated with disease risk and clinical outcomes. However, GWAS has only rarely revealed information on the exact genetic elements and their effects underlying an association because the majority of the hits are within non-coding regions. Some of the variants or the linked polymorphisms are now being discovered to have functional significance, such as regulatory elements in the promoter and enhancer regions or the microRNA binding sites in the 3′untranslated region of the protein-coding genes, which influence transcription, RNA stability, and translation of the protein-coding genes. However, only 3% of the entire transcriptome is protein-coding, signifying that non-coding RNAs represent most of the transcripts. Thus, a large portion of previously identified intergenic GWAS single nucleotide polymorphisms (SNPs) is in the non-coding RNAs. The non-coding RNAs form a large-scale regulatory network across the transcriptome, greatly expanding the complexity of gene regulation. Accumulating evidence also suggests that the “non-coding” genome regions actively regulate the highly dynamic three dimensional (3D) chromatin structures, which are critical for genome function. Epigenetic modulation like DNA methylation and histone modifications further affect chromatin accessibility and gene expression adding another layer of complexity to the functional interpretation of genetic variation associated with disease outcomes. We provide an overview of the current information on the influence of variation in these “untranslated” regions of the human genome on infectious diseases. The focus of this review is infectious disease-associated polymorphisms and gene regulatory mechanisms of pathophysiological relevance.
In the version of this article initially published, the right two labels along the horizontal axis of Fig. 8c (IntA and IntG) were in the incorrect order. The correct order is IntG (middle right) and IntA (far right). The error has been corrected in the HTML and PDF versions of the article.
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