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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]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149161 | GEO | 2020/04/23

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 [MPRA NGS]

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.

2020-04-20 | GSE129242 | 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 with multi-layer annotation identified cell-type-specific functional variants and genes associated with melanoma (MPRA)

Project description:The most recent genome-wide association study (GWAS) of cutaneous melanoma identified 54 risk-associated loci, but functional variants and their target genes for most have not been established. Here, we performed massively parallel reporter assays (MPRA) using malignant melanoma and normal melanocyte cells and further integrated multi-layer annotation to systematically prioritize functional variants and susceptibility genes from these GWAS loci. Of 1,992 risk-associated variants tested in MPRA, we identified 285 from 42 loci (78% of the known loci) displaying significant allelic transcriptional activities in either cell type (FDR < 1%). We further characterized MPRA-significant variants by motif prediction, epigenomic annotation, and statistical/functional fine-mapping to create integrative variant scores, which prioritized one to six plausible candidate variants per locus for the 42 loci and nominated a single variant for 43% of these loci. Overlaying the MPRA-significant variants with genome-wide significant expression or methylation quantitative trait loci (QTLs) from melanocytes or melanomas identified candidate susceptibility genes for 60% of variants (172 of 285 variants). CRISPRi of top-scoring variants validated their cis-regulatory effect on the eQTL target genes, MAFF (22q13.1) and GPRC5A (12p13.1). Finally, we identified 36 melanoma-specific and 45 melanocyte-specific MPRA-significant variants, a subset of which are linked to cell-type-specific target genes. Analyses of transcription factor availability in MPRA datasets and variant-transcription factor interaction in eQTL datasets highlighted the roles of transcription factors in cell-type-specific variant functionality. In conclusion, MPRA along with variant scoring effectively prioritized plausible candidates for most melanoma GWAS loci and highlighted cellular contexts where the susceptibility variants are functional.

2022-11-28 | GSE210354 | GEO

Massively parallel reporter assays with multi-layer annotation identified cell-type-specific functional variants and genes associated with melanoma (RNA-Seq)

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Differential allelic expression in normal breast tissue

Project description:Most loci contributing to breast cancer susceptibility identified by the recent genome-wide association studies (GWAS) are predicted to have a regulatory function. Additionally, the early phases of the GWAS studies have generated long lists of possible candidates that need to be prioritised for follow-up studies. Integration of allelic expression mapping and disease association data should enable the identification of those GWAS hits with higher cis-regulatory potential. Our aims are (1) to assess how well functional data and disease risk are correlated and (2) to help prioritise and select the strongest candidates from the GWAS scan for further follow-up and functional analysis. We are performing genome-wide differential allelic expression (DAE) analysis to identify loci with cis-regulatory potential in sixty-four normal breast tissue samples. Using the Illumina Exon510S-Duo BeadChips, we have identified 34K informative SNPs of which approximately 8K (23.5%) displayed DAE. Two SNPs showed monoallelic expression suggesting possible new imprinted loci. We are mapping the cis-regulatory loci by fitting a linear regression model with permutations to DAE ratios vs genotype at SNPs within ±250kb of the RefSeq gene corresponding to the DAE SNP. We will combine our data with the UK GWAS1 and GWAS2 studies for breast cancer susceptibility, to generate a list of genes that show regulatory variation for further evaluation as candidates. This is the first genome-wide differential allelic expression study in normal breast tissue, and one of the first in a primary tissue. We predict that this will be a powerful approach to validate/identify susceptibility loci and to unravel some of the biology underlying breast cancer susceptibility. Allelic gene expression of normal breast sample from healthy controls.

2012-05-02 | E-GEOD-35023 | biostudies-arrayexpress

Cell-type specific meQTL extends melanoma GWAS annotation beyond eQTL and identifies a melanocyte gene regulatory network

Project description:To explore the roles of cell-type specific methylation QTL (meQTL) for melanoma GWAS annotation, we generated DNA methylation data from the same sample set as our previouse eQTL study including 106 primary melanocyte cultures. The Illumina Infinium 450k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 480,000 CpGs in 106 primary melanocyte cultures. To be able to identify the DNA methylation probes whose methylation levels are correlated with germline genetic variants including the ones associated with melanoma, meQTL analysis was performed in these 106 primary melanocyte cultures using the same method as we did for eQTL study.

2021-10-01 | GSE166069 | GEO

Differential allelic expression in normal breast tissue

2012-05-03 | GSE35023 | GEO

ChIP-seq for EP300 and H3K4me1 in the mouse melanocyte cell line melan-a

Project description:Using ChIP-seq for p300 and H3K4me1, we identified 2,489 putative melanocyte enhancer loci in the mouse genome. We demonstrated that these putative enhancers are evolutionarily constrained, enriched for sequence motifs predicted to bind key melanocyte transcription factors, located near genes relevant to melanocyte biology, and capable of driving reporter gene expression with high frequency in cultured melanocytes and in melanocytes of transgenic zebrafish. ChIP-seq for EP300 and H3K4me1 in the mouse melanocyte cell line melan-a.

2012-09-14 | E-GEOD-38498 | biostudies-arrayexpress

Transcriptional-Regulatory Convergence Across Functional MDD Risk Variants Identified by Massively Parallel Reporter Assays [Expt1]

Project description:Using Massively Parallel Reporter Assays (MPRAs), we functionally screened over 1,000 SNPs, prioritized from 39 neuropsychiatric trait/disease GWAS loci based on overlap with predicted regulatory features—including expression quantitative trait loci (eQTL) and histone marks—from human brains and cell cultures. Using mouse neuroblastoma Neuro2a (N2a) cells, we identify over 100 SNPs with allelic effects on expression. Functional SNPs were enriched for binding sequences of retinoic acid-receptive transcription factors (TFs); with additional allelic differences unmasked in cells treated with all-trans retinoic acid (ATRA). Motifs overrepresented at functional SNPs corresponded to a set of TFs highly specific to serotonergic neurons and collectively downregulated in schizophrenia. Our application of MPRAs to screen MDD-associated SNPs suggested a shared transcriptional regulatory program across loci, a subset of which are unmasked by retinoids. Additional code and results corresponding to this GEO submission can be found at https://bitbucket.org/jdlabteam/n2a_atra_mdd_mpra_paper/src

2021-06-30 | GSE167517 | GEO

UV effects in mouse melanocytes

Project description:Ultraviolet (UV) radiation is a major melanoma risk factor, yet underlying mechanisms remain poorly understood. Here we introduce a mouse model permitting fluorescence-aided melanocyte imaging and isolation following in vivo UV irradiation. We use expression profiling to show that activated neonatal skin melanocytes isolated following a melanomagenic UVB dose bear a distinct, persistent interferon-response signature, including genes associated with immunoevasion. UVB-induced melanocyte activation, characterized by aberrant growth and migration, was abolished by antibody-mediated systemic blockade of interferon-gamma (IFN-gamma), but not type-I interferons. IFN-gamma was produced by macrophages recruited to neonatal skin by UVB-induced chemokine receptor Ccr2 ligands. Admixed recruited skin macrophages enhanced transplanted melanoma growth by inhibiting apoptosis; notably, IFN-gamma blockade abolished macrophage-associated melanoma growth and survival. IFN-gamma-producing macrophages were identified in 70% of human melanomas examined. Our data reveal an unanticipated role for IFN-gamma in promoting melanocytic cell survival/immunoevasion, and suggest IFN-gamma-R signaling represents a novel therapeutic melanoma target. Biologic replicates of UVA- and UVB-treated mouse melanocytes, as well as untreated mouse melanocytes and mouse keratinocytes, were used to define melanocyte expression signatures associated with UV treatment.

2011-01-01 | E-GEOD-25164 | biostudies-arrayexpress

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