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A biallelic multiple nucleotide length polymorphism explains functional causality at 5p15.33 prostate cancer risk locus [RNA-Seq]

ABSTRACT: To date, single-nucleotide polymorphisms (SNPs) have been the most intensively investigated class of polymorphisms in genome wide associations studies (GWAS), however, other classes such as insertion-deletion or multiple nucleotide length polymorphism (MNLPs) may also confer disease risk. Multiple reports have shown that the 5p15.33 prostate cancer (PCa) risk region is a particularly strong expression quantitative trait locus (eQTL) for IRX4 transcripts. Here, we demonstrate using epigenome and genome editing that a biallelic (47bp/21bp) MNLP is the causal variant regulating IRX4 transcript levels. In LNCaP PCa cells (homozygous for the short allele), a single copy knock-in of the long allele potently alters the chromatin state, enabling de novo functional binding of the androgen receptor (AR) associated with increased chromatin accessibility, H3K27 acetylation, and ~3-fold upregulation of IRX4 expression. We further show that an MNLP is amongst the strongest candidate susceptibility variants at two additional PCa risk loci. We estimated that at least 5% of PCa risk loci could be explained by functional non-SNP causal variants, which may have broader implications for other cancers GWAS. More generally, our results underscore the importance of investigating other classes of inherited variation as causal mediators of human traits.

ORGANISM(S): Homo sapiens

PROVIDER: GSE231747 | GEO | 2023/07/11

REPOSITORIES: GEO

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A biallelic multiple nucleotide length polymorphism explains functional causality at the 5p15.33 prostate cancer risk locus [ChIP-Seq]

Project description:To date, single-nucleotide polymorphisms (SNPs) have been the most intensively investigated class of polymorphisms in genome wide associations studies (GWAS), however, other classes such as insertion-deletion or multiple nucleotide length polymorphism (MNLPs) may also confer disease risk. Multiple reports have shown that the 5p15.33 prostate cancer (PCa) risk region is a particularly strong expression quantitative trait locus (eQTL) for IRX4 transcripts. Here, we demonstrate using epigenome and genome editing that a biallelic (47bp/21bp) MNLP is the causal variant regulating IRX4 transcript levels. In LNCaP PCa cells (homozygous for the short allele), a single copy knock-in of the long allele potently alters the chromatin state, enabling de novo functional binding of the androgen receptor (AR) associated with increased chromatin accessibility, H3K27 acetylation, and ~3-fold upregulation of IRX4 expression. We further show that an MNLP is amongst the strongest candidate susceptibility variants at two additional PCa risk loci. We estimated that at least 5% of PCa risk loci could be explained by functional non-SNP causal variants, which may have broader implications for other cancers GWAS. More generally, our results underscore the importance of investigating other classes of inherited variation as causal mediators of human traits.

2023-07-11 | GSE231748 | GEO

A biallelic multiple nucleotide length polymorphism explains functional causality at the 5p15.33 prostate cancer risk locus [ATAC-Seq]

2023-07-11 | GSE231750 | GEO

Integrative functional genomics identifies an enhancer looping to the SOX9 gene disrupted by the 17q24.3 prostate cancer risk locus

Project description:Genome-wide association studies (GWAS) are identifying genetic predisposition to various diseases. The rs1859962 single nucleotide polymorphism (SNP) part of the 17q24.3 locus is a risk factor for prostate cancer (PCa). It defines a 130kb linkage disequilibrium (LD) block that lies in a ~2Mb gene desert area. Despite a role for the proximal SOX9 gene in PCa development, the functional biology driving the risk of this 17q24.3 risk locus is unknown. In the present study, we integrate genome-wide chromatin landscape datasets, namely epigenomes and chromatin openness from diverse cell-types to identify one PCa specific enhancer within the rs1859962 risk LD block. We reveal that this enhancer is part of a 1Mb chromatin loop with the SOX9 gene in PCa cells. The rs8072254 and rs1859961 SNPs part of this LD block map to this enhancer and impose allele-specific gene expression. The variant allele of rs1859961 directly decreases FoxA1 binding while increasing AP-1 binding compared to the reference allele. This latter is key in driving allele-specific gene expression. Together, our results demonstrate the risk associated with the PCa rs1859962 risk LD block is accounted for by multiple genetic variants mapping to a unique enhancer looping to the SOX9 oncogene. Allele-specific recruitment of the transcription factor AP-1 accounts in part for the increased enhancer activity ascribed to this PCa risk LD block. This further demonstrates that an integrative genomics approach can identify the functional biology disrupted by genetic risk-variants. Examination of histone modification H3K36me3 in the prostate cancer LNCaP cell line under DHT treatment.

2012-06-03 | E-GEOD-35829 | biostudies-arrayexpress

Prostate Cancer Risk SNPs enriched in Androgen Receptor Binding Sites

Project description:Genome-wide association studies (GWAS) have identified dozens of genomic loci, whose single nucleotide polymorphisms (SNPs) predispose to prostate cancer (PCa). However, the biological functions of these common genetic variants and the mechanisms to increase disease risk are largely unknown. We integrated chromatin-IP coupled sequencing (ChIP-seq) and microarray expression profiling in the TMPRSS2-ERG gene rearrangement positive DuCaP cell model with the NHGRI GWAS PCa risk SNPs catalog, in an attempt to identify disease susceptibility SNPs localized within functional androgen receptor binding sites (ARBSs). Among the 48 GWAS index SNPs and 2,702 linked SNPs defined by the 1000G project 104 were found to be localized in the AR ChIP-seq peaks. Of these risk SNPs, rs11891426 T/G in the 7th intron of its host gene melanophilin (MLPH) was found located within a putative auxiliary ARE motif, which we found enriched in the neighborhood of canonical ARE motifs. Exchange of T to G attenuated the transcriptional activity of the MLPH-ARBS in a reporter gene assay. The expression of MLPH protein in tissue samples from prostate cancer patients was significantly lower in those with the G compared to the T allele. Moreover, a significant positive correlation of AR and MLPH protein expression levels was also confirmed in tissue samples. These results unravel a hidden link between AR and a functional PCa risk SNP rs11891426, whose allele alteration affects androgen regulation of its host gene MLPH. This study shows the power of integrative studies to pin down functional risk SNPs and justifies further investigations.

2015-10-12 | GSE63693 | GEO

Integrative functional genomics identifies an enhancer looping to the SOX9 gene disrupted by the 17q24.3 prostate cancer risk locus

2012-06-03 | GSE35829 | GEO

Restless Legs Syndrome-associated variant in MEIS1 confers altered gene expression in embryonic ganglionic eminences

Project description:Genome-wide association studies (GWASs) identified the MEIS1 locus for Restless Legs Syndrome (RLS), but causal single nucleotide polymorphisms (SNPs) and the functional relevance have remained to be elucidated. The MEIS1 locus contains an exceptionally large number of highly conserved non-coding regions (HCNRs), which potentially function as cis-regulatory modules. We analyzed the HCNRs in the RLS-associated linkage disequilibrium (LD) block for allele-dependent enhancer activity in both zebrafish and mouse, comparing the protective and risk alleles of RLS-associated common variants. We found one enhancer, harboring the lead SNP rs12469063, which showed an allele-dependent reduction of reporter gene expression exclusively in the embryonic ganglionic eminences at developmental stage E12.5. Notably, the reporter activity overlapped with the endogenous telencephalic Meis1 expression domain, which co-localized with transcripts of all four validated RLS loci. Thus, the developing telencephalon represents the first neuroanatomic region implicated for RLS based on GWAS findings. Total RNA obtained from 2-3 male and female mice E12.5 (wildtype, heterzygote, homozygote) and 3-4 male heterozygote and wildtype mice (adult)

2014-01-29 | E-GEOD-44592 | biostudies-arrayexpress

Prostate Cancer Risk SNPs in Androgen Receptor Target Sites

Project description:We profiled androgen receptor (AR) genomic targets using high-throughput sequencing of chromatin-immunoprecipitated (ChIP) DNA from TMPRSS2-ERG fusion gene positive DUCaP prostate cancer cells. ChIp-seq and microarray gene expression profiling datasets were integrated with the NHGRI GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor binding sites (ARBSs). Eighty GWAS index or linked SNPs were found to be localized in ARBSs. Among these rs11891426:T>G in the 7th intron of the melanophilin gene was found located within a novel putative auxiliary AR binding motif, which we found enriched in the neighborhood of canonical androgen responsive elements. T→G exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay of prostate cancer cell models. It went also in line with decreased melanophilin protein level in primary prostate tumors with G allele.These results unravel a hidden link between androgen receptor and a functional PCa risk SNP, whose allele alteration affects androgen regulation of its host gene melanophilin . Genomic profile of androgen receptor binding sites of androgen or vehicle treated DUCaP cells using ChIP-seq. IgG precipiated DNAs from both treatments served as controls.

2015-07-10 | E-GEOD-70679 | biostudies-arrayexpress

Restless Legs Syndrome-associated variant in MEIS1 confers altered gene expression in embryonic ganglionic eminences

2014-01-29 | GSE44592 | GEO

Genetic Risk Variants for Autoimmune Diseases that Influence Gene Expression in Thymus

Project description:Genome-wide association studies (GWAS) have boosted our knowledge of genetic risk variants in autoimmune diseases (AIDs). Most of the risk variants are located within or near genes with immunological functions, and the majority is found to be non-coding, pointing towards a regulatory role. We have performed a cis expression quantitative trait locus (eQTL) screen to investigate whether single nucleotide polymorphisms (SNPs) associated with AIDs influence gene expression in thymus. Genotyping was performed using the Immunochip and 353 AID associated SNPs were tested against expression of surrounding genes (+/- 1 Mb) from human thymic tissue (N=42). We identified eight genes where the expression was associated with AID risk SNPs at a study-wide level of significance (P < 2.57x10-5). Five genes (FCRL3, RNASET2, C2orf74, SIRPG and SYS1) displayed cis eQTL signals also in other tissues, while for two loci (NPIPB8 and LOC388814), the eQTL signal appear to be thymus-specific. Since many AID risk variants from GWAS have been subsequently fine-mapped in recent Immunochip projects, we explored the overlap between these novel AID risk variants and the thymic eQTL regions. Moreover, we examined the functional annotation of the seven expression altering SNPs (eSNPs). Our study reveals autoimmune risk variants that act as eQTLs in thymus. We have highlighted functional variants within these genetic regions that potentially can represent causal autoimmune risk variants. Total RNA from 42 human thymic samples were obtained from children undergoing cardiac surgery.

2016-01-21 | E-GEOD-77052 | biostudies-arrayexpress

CRISPR-mediated deletion of prostate cancer risk-associated CTCF loop anchors identifies repressive chromatin loops

Project description:Background: Recent genome-wide association studies (GWAS) have identified more than 100 loci associated with increased risk of prostate cancer, most of which are in non-coding regions of the genome. Understanding the function of these non-coding risk loci is critical to elucidate the genetic susceptibility to prostate cancer. Results: We generated genome-wide regulatory element maps and performed genome-wide chromosome confirmation capture assays (in situ Hi-C) in normal and tumorigenic prostate cells. Using this information, we annotated the regulatory potential of 2,181 fine-mapped PCa risk-associated SNPs and predicted a set of target genes that are regulated by PCa risk-related H3K27Ac-mediated loops. We next identified PCa risk-associated CTCF sites involved in long-range chromatin loops. We used CRISPR-mediated deletion to remove PCa risk-associated CTCF anchor regions and the CTCF anchor regions looped to the PCa risk-associated CTCF sites; we observed up to 100 fold increases in expression of genes within the loops when the PCa risk-associated CTCF anchor regions were deleted. Conclusions: We have identified GWAS risk loci involved in long-range loops that function to repress gene expression within chromatin loops. Our studies provide new insights into the genetic susceptibility to prostate cancer.

2018-08-15 | GSE118514 | GEO

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