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Massively parallel reporter assays combined with cell-type specific eQTL identified a functional melanoma risk variant in HIV-1 restriction gene, MX2

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE129250 | GEO | 2020/04/20

REPOSITORIES: GEO

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Massively parallel reporter assays combined with cell-type specific eQTL identified a functional melanoma risk variant in HIV-1 restriction gene, MX2 [MX2_overexpress_time]

Project description:Genome-wide association studies (GWAS) have identified twenty melanoma susceptibility loci. To identify susceptibility genes and variants simultaneously from multiple GWAS loci, we integrated massively-parallel reporter assays (MPRA) with melanocyte-specific expression quantitative trait locus (eQTL) profiling. We identified thirty-nine candidate functional variants displaying allelic transcriptional activity, of which nine from four loci were also correlated with local gene expression in melanocytes (CTSS, CASP8, MX2, and MAFF). Among these, we further characterized the locus in MX2 gene on chromosome band Chr21q22.3 and validated a functional variant, rs398206. The functional variant mediates allelic transcriptional activity via binding of the transcription factor, YY1. This allelic transcriptional regulation largely accounts for a significant cis-eQTL of the HIV-1 restriction gene, MX2, in primary melanocytes, where the melanoma risk-associated A allele is correlated with higher MX2 levels. Melanocyte-specific transgenic expression of human MX2 in a zebrafish model demonstrated an accelerated melanoma formation in a BRAFV600E background. Thus, using an efficient scalable approach to streamline GWAS follow-up functional studies, we uncovered a pleiotropic function of MX2 in melanoma susceptibility.

2020-04-23 | GSE149161 | GEO

Massively parallel reporter assays combined with cell-type specific eQTL identified a functional melanoma risk variant in HIV-1 restriction gene, MX2 [MX2_overexpress]

2020-04-20 | GSE129237 | GEO

Massively parallel reporter assays combined with cell-type specific eQTL identified a functional melanoma risk variant in HIV-1 restriction gene, MX2 [MPRA NGS]

2020-04-20 | GSE129242 | GEO

Massively parallel reporter assays of melanoma risk variants identify MX2 as a gene promoting melanoma.

Project description:Genome-wide association studies (GWAS) have identified ~20 melanoma susceptibility loci, most of which are not functionally characterized. Here we report an approach integrating massively-parallel reporter assays (MPRA) with cell-type-specific epigenome and expression quantitative trait loci (eQTL) to identify susceptibility genes/variants from multiple GWAS loci. From 832 high-LD variants, we identify 39 candidate functional variants from 14 loci displaying allelic transcriptional activity, a subset of which corroborates four colocalizing melanocyte cis-eQTL genes. Among these, we further characterize the locus encompassing the HIV-1 restriction gene, MX2 (Chr21q22.3), and validate a functional intronic variant, rs398206. rs398206 mediates the binding of the transcription factor, YY1, to increase MX2 levels, consistent with the cis-eQTL of MX2 in primary human melanocytes. Melanocyte-specific expression of human MX2 in a zebrafish model demonstrates accelerated melanoma formation in a BRAFV600E background. Our integrative approach streamlines GWAS follow-up studies and highlights a pleiotropic function of MX2 in melanoma susceptibility.

| S-EPMC7264232 | biostudies-literature

Massively parallel reporter assays combined with cell-type specific eQTL identified a functional melanoma risk variant in HIV-1 restriction gene, MX2

Project description:Massively parallel reporter assays combined with cell-type specific eQTL identified a functional melanoma risk variant in HIV-1 restriction gene, MX2

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Massively parallel reporter assays combined with cell-type specific eQTL identified a functional melanoma risk variant in HIV-1 restriction gene, MX2 [MX2_overexpress]

Project description:Massively parallel reporter assays combined with cell-type specific eQTL identified a functional melanoma risk variant in HIV-1 restriction gene, MX2 [MX2_overexpress]

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Massively parallel reporter assays combined with cell-type specific eQTL identified a functional melanoma risk variant in HIV-1 restriction gene, MX2 [MX2_overexpress_time]

Project description:Massively parallel reporter assays combined with cell-type specific eQTL identified a functional melanoma risk variant in HIV-1 restriction gene, MX2 [MX2_overexpress_time]

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Massively parallel reporter assays combined with cell-type specific eQTL identified a functional melanoma risk variant in HIV-1 restriction gene, MX2 [MPRA NGS]

Project description:Massively parallel reporter assays combined with cell-type specific eQTL identified a functional melanoma risk variant in HIV-1 restriction gene, MX2 [MPRA NGS]

| PRJNA530577 | ENA

Transcriptional-regulatory convergence across functional MDD risk variants identified by massively parallel reporter assays.

Project description:Family and population studies indicate clear heritability of major depressive disorder (MDD), though its underlying biology remains unclear. The majority of single-nucleotide polymorphism (SNP) linkage blocks associated with MDD by genome-wide association studies (GWASes) are believed to alter transcriptional regulators (e.g., enhancers, promoters) based on enrichment of marks correlated with these functions. A key to understanding MDD pathophysiology will be elucidation of which SNPs are functional and how such functional variants biologically converge to elicit the disease. Furthermore, retinoids can elicit MDD in patients and promote depressive-like behaviors in rodent models, acting via a regulatory system of retinoid receptor transcription factors (TFs). We therefore sought to simultaneously identify functional genetic variants and assess retinoid pathway regulation of MDD risk loci. Using Massively Parallel Reporter Assays (MPRAs), we functionally screened over 1000 SNPs prioritized from 39 neuropsychiatric trait/disease GWAS loci, selecting SNPs based on overlap with predicted regulatory features-including expression quantitative trait loci (eQTL) and histone marks-from human brains and cell cultures. We identified >100 SNPs with allelic effects on expression in a retinoid-responsive model system. Functional SNPs were enriched for binding sequences of retinoic acid-receptive transcription factors (TFs), with additional allelic differences unmasked by treatment with all-trans retinoic acid (ATRA). Finally, motifs overrepresented across functional SNPs corresponded to TFs highly specific to serotonergic neurons, suggesting an in vivo site of action. Our application of MPRAs to screen MDD-associated SNPs suggests a shared transcriptional-regulatory program across loci, a component of which is unmasked by retinoids.

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Leveraging massively parallel reporter assays for evolutionary questions.

Project description:A long-standing goal of evolutionary biology is to decode how gene regulation contributes to organismal diversity. Doing so is challenging because it is hard to predict function from non-coding sequence and to perform molecular research with non-model taxa. Massively parallel reporter assays (MPRAs) enable the testing of thousands to millions of sequences for regulatory activity simultaneously. Here, we discuss the execution, advantages, and limitations of MPRAs, with a focus on evolutionary questions. We propose solutions for extending MPRAs to rare taxa and those with limited genomic resources, and we underscore MPRA's broad potential for driving genome-scale, functional studies across organisms.

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