scholarly journals The prostate cancer risk variant rs55958994 regulates multiple gene expression through extreme long-range chromatin interaction to control tumor progression

2019 ◽  
Vol 5 (7) ◽  
pp. eaaw6710 ◽  
Author(s):  
Yuyang Qian ◽  
Lei Zhang ◽  
Mingyang Cai ◽  
Hongxia Li ◽  
Heming Xu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Long Range ◽  
Cancer Progression ◽  
Target Genes ◽  
Association Studies ◽  
Prostate Cancer Risk ◽  
Chromatin Interaction ◽  
Genome Wide Association Studies ◽  
Chromosome Conformation ◽  
Increased Risk

Genome-wide association studies identified single-nucleotide polymorphism (SNP) rs55958994 as a significant variant associated with increased susceptibility to prostate cancer. However, the mechanisms by which this SNP mediates increased risk to cancer are still unknown. In this study, we show that this variant is located in an enhancer active in prostate cancer cells. Deletion of this enhancer from prostate tumor cells resulted in decreased tumor initiation, tumor growth, and invasive migration, as well as a loss of stem-like cells. Using a combination of capture chromosome conformation capture (Capture-C) and RNA sequencing, we identified genes on the same and different chromosomes as targets regulated by the enhancer. Furthermore, we show that expression of individual candidate target genes in an enhancer-deleted cell line rescued different aspects of tumorigenesis. Our data suggest that the rs55958994-associated enhancer affects prostate cancer progression by influencing expression of multiple genes via long-range chromatin interactions.

scholarly journals Parallel Reporter Assays Identify Altered Regulatory Role of rs684232 in Leading to Prostate Cancer Predisposition

2021 ◽  
Vol 22 (16) ◽  
pp. 8792
Author(s):  
Naixia Ren ◽  
Qingqing Liu ◽  
Lingjie Yan ◽  
Qilai Huang
Keyword(s):  
Prostate Cancer ◽  
Cancer Risk ◽  
Cancer Progression ◽  
Association Studies ◽  
Functional Characterization ◽  
Prostate Cancer Risk ◽  
Underlying Mechanism ◽  
Great Promise ◽  
Genome Wide Association Studies ◽  
Regulatory Snps

Functional characterization of cancer risk-associated single nucleotide polymorphism (SNP) identified by genome-wide association studies (GWAS) has become a big challenge. To identify the regulatory risk SNPs that can lead to transcriptional misregulation, we performed parallel reporter gene assays with both alleles of 213 prostate cancer risk-associated GWAS SNPs in 22Rv1 cells. We disclosed 32 regulatory SNPs that exhibited different regulatory activities with two alleles. For one of the regulatory SNPs, rs684232, we found that the variation altered chromatin binding of transcription factor FOXA1 on the DNA region and led to aberrant gene expression of VPS53, FAM57A, and GEMIN4, which play vital roles in prostate cancer malignancy. Our findings reveal the roles and underlying mechanism of rs684232 in prostate cancer progression and hold great promise in benefiting prostate cancer patients with prognostic prediction and target therapies.

scholarly journals Long-range Pitx2c enhancer–promoter interactions prevent predisposition to atrial fibrillation

2019 ◽  
Vol 116 (45) ◽  
pp. 22692-22698 ◽  
Author(s):  
Min Zhang ◽  
Matthew C. Hill ◽  
Zachary A. Kadow ◽  
Ji Ho Suh ◽  
Nathan R. Tucker ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Long Range ◽  
Association Studies ◽  
Ctcf Binding ◽  
Ctcf Binding Site ◽  
Genome Wide Association Studies ◽  
Range Interaction ◽  
Chromosome Conformation ◽  
Risk Variants ◽  
Increased Risk

Genome-wide association studies found that increased risk for atrial fibrillation (AF), the most common human heart arrhythmia, is associated with noncoding sequence variants located in proximity to PITX2. Cardiomyocyte-specific epigenomic and comparative genomics uncovered 2 AF-associated enhancers neighboring PITX2 with varying conservation in mice. Chromosome conformation capture experiments in mice revealed that the Pitx2c promoter directly contacted the AF-associated enhancer regions. CRISPR/Cas9-mediated deletion of a 20-kb topologically engaged enhancer led to reduced Pitx2c transcription and AF predisposition. Allele-specific chromatin immunoprecipitation sequencing on hybrid heterozygous enhancer knockout mice revealed that long-range interaction of an AF-associated region with the Pitx2c promoter was required for maintenance of the Pitx2c promoter chromatin state. Long-range looping was mediated by CCCTC-binding factor (CTCF), since genetic disruption of the intronic CTCF-binding site caused reduced Pitx2c expression, AF predisposition, and diminished active chromatin marks on Pitx2. AF risk variants located at 4q25 reside in genomic regions possessing long-range transcriptional regulatory functions directed at PITX2.

scholarly journals Integrative Genomic Analysis for the Discovery of Biomarkers in Prostate Cancer

2014 ◽  
Vol 9 ◽  
pp. BMI.S13729 ◽  
Author(s):  
Chindo Hicks ◽  
Tejaswi Koganti ◽  
Shankar Giri ◽  
Memory Tekere ◽  
Ritika Ramani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Gene Expression Data ◽  
Genetic Variants ◽  
Association Studies ◽  
Biological Pathways ◽  
Great Success ◽  
Genome Wide Association Studies ◽  
Expression Data ◽  
Increased Risk

Genome-wide association studies (GWAS) have achieved great success in identifying single nucleotide polymorphisms (SNPs, herein called genetic variants) and genes associated with risk of developing prostate cancer. However, GWAS do not typically link the genetic variants to the disease state or inform the broader context in which the genetic variants operate. Here, we present a novel integrative genomics approach that combines GWAS information with gene expression data to infer the causal association between gene expression and the disease and to identify the network states and biological pathways enriched for genetic variants. We identified gene regulatory networks and biological pathways enriched for genetic variants, including the prostate cancer, IGF-1, JAK2, androgen, and prolactin signaling pathways. The integration of GWAS information with gene expression data provides insights about the broader context in which genetic variants associated with an increased risk of developing prostate cancer operate.

scholarly journals Validation of prostate cancer risk variants by CRISPR/Cas9 mediated genome editing

2018 ◽  
Author(s):  
Xing Wang ◽  
James E. Hayes ◽  
Xing Xu ◽  
Xiaoni Gao ◽  
Dipti Mehta ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Cancer Risk ◽  
Association Studies ◽  
Prostate Cancer Risk ◽  
Genome Wide Association Studies ◽  
Single Nucleotide ◽  
Cancer Pathogenesis ◽  
Risk Variants ◽  
Specific Manner

AbstractGWAS have identified numerous SNPs associated with prostate cancer risk. One such SNP is rs10993994. It is located in the MSMB promoter, associates with MSMB encoded β-microseminoprotein prostate secretion levels, and is associated with mRNA expression changes in MSMB and the adjacent gene NCOA4. In addition, our previous work showed a second SNP, rs7098889, is in LD with rs10993994 and associated with MSMB expression independent of rs10993994. Here, we generate a series of clones with single alleles removed by double guide RNA (gRNA) mediated CRISPR/Cas9 deletions, through which we demonstrate that each of these SNPs independently and greatly alters MSMB expression in an allele-specific manner. We further show that these SNPs have no substantial effect on the expression of NCOA4. These data demonstrate that a single SNP can have a large effect on gene expression and illustrate the importance of functional validation to deconvolute observed correlations. The method we have developed is generally applicable to test any SNP for which a relevant heterozygous cell line is available.Author summaryIn pursuing the underlying biological mechanism of prostate cancer pathogenesis, scientists utilized the existence of common single nucleotide polymorphisms (SNPs) in human genome as genetic markers to perform large scale genome wide association studies (GWAS) and have so far identified more than a hundred prostate cancer risk variants. Such variants provide an unbiased and systematic new venue to study the disease mechanism, and the next big challenge is to translate these genetic associations to the causal role of altered gene function in oncogenesis. The majority of these variants are waiting to be studied and lots of them may act in oncogenesis through gene expression regulation. To prove the concept, we took rs10993994 and its linked rs7098889 as an example and engineered single cell clones by allelic-specific CRISPR/Cas9 deletion to separate the effect of each allele. We observed that a single nucleotide difference would lead to surprisingly high level of MSMB gene expression change in a gene specific and tissue specific manner. Our study strongly supports the notion that differential level of gene expression caused by risk variants and their associated genetic locus play a major role in oncogenesis and also highlights the importance of studying the function of MSMB encoded β-MSP in prostate cancer pathogenesis.

scholarly journals Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation

2021 ◽  
Author(s):  
Sylvan C Baca ◽  
Cassandra Singler ◽  
Soumya Zacharia ◽  
Ji-Heui Seo ◽  
Tunc Morova ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Steady State ◽  
Binding Sites ◽  
Association Studies ◽  
Prostate Cancer Risk ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Context Dependent

Methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs), are widely used to functionally annotate trait-associated variants, but they are limited in identifying context-dependent effects on transcription. To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for nominating variants that impact traits through their effects on chromatin state. CWAS associates the genetic determinants of cistromes (e.g., the genome-wide profiles of transcription factor binding sites or histone modifications) with traits using summary statistics from genome-wide association studies (GWAS). We performed CWASs of prostate cancer and androgen-related traits, using a reference panel of 307 prostate cistromes from 165 individuals. CWAS nominated susceptibility regulatory elements or androgen receptor (AR) binding sites at 52 out of 98 known prostate cancer GWAS loci and implicated an additional 17 novel loci. We functionally validated a subset of our results using CRISPRi and in vitro reporter assays. At 28 of the 52 risk loci, CWAS identified regulatory mechanisms that are not observable via eQTLs, implicating genes with complex or context-specific regulation that are overlooked by current approaches that relying on steady-state transcript measurements. CWAS genes include transcription factors that govern prostate development such as NKX3-1, HOXB13, GATA2, and KLF5. Moreover, CWAS boosts discovery power in modestly sized GWAS, identifying novel genetic associations mediated through AR binding for androgen-related phenotypes, including resistance to prostate cancer therapy. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting context-dependent transcriptional regulation.

scholarly journals Post genome-wide association studies functional characterization of prostate cancer risk loci

BMC Genomics ◽  
2013 ◽  
Vol 14 (Suppl 8) ◽  
pp. S9 ◽  
Author(s):  
Junfeng Jiang ◽  
Weirong Cui ◽  
Wanwipa Vongsangnak ◽  
Guang Hu ◽  
Bairong Shen
Keyword(s):  
Prostate Cancer ◽  
Cancer Risk ◽  
Association Studies ◽  
Functional Characterization ◽  
Prostate Cancer Risk ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

scholarly journals Understanding the genetics of neuropsychiatric disorders: the potential role of genomic regulatory blocks

2019 ◽  
Vol 25 (1) ◽  
pp. 6-18 ◽  
Author(s):  
Anja Barešić ◽  
Alexander Jolyon Nash ◽  
Tarik Dahoun ◽  
Oliver Howes ◽  
Boris Lenhard
Keyword(s):  
Long Range ◽  
Developmental Disorders ◽  
Target Genes ◽  
Association Studies ◽  
Three Dimensional ◽  
Neuropsychiatric Disorders ◽  
Autism Spectrum ◽  
Genome Wide Association Studies ◽  
Genomic Context ◽  
Coding Regions

Abstract Recent genome-wide association studies have identified numerous loci associated with neuropsychiatric disorders. The majority of these are in non-coding regions, and are commonly assigned to the nearest gene along the genome. However, this approach neglects the three-dimensional organisation of the genome, and the fact that the genome contains arrays of extremely conserved non-coding elements termed genomic regulatory blocks (GRBs), which can be utilized to detect genes under long-range developmental regulation. Here we review a GRB-based approach to assign loci in non-coding regions to potential target genes, and apply it to reanalyse the results of one of the largest schizophrenia GWAS (SWG PGC, 2014). We further apply this approach to GWAS data from two related neuropsychiatric disorders—autism spectrum disorder and bipolar disorder—to show that it is applicable to developmental disorders in general. We find that disease-associated SNPs are overrepresented in GRBs and that the GRB model is a powerful tool for linking these SNPs to their correct target genes under long-range regulation. Our analysis identifies novel genes not previously implicated in schizophrenia and corroborates a number of predicted targets from the original study. The results are available as an online resource in which the genomic context and the strength of enhancer–promoter associations can be browsed for each schizophrenia-associated SNP.

Genetically proxied morning chronotype was associated with a reduced risk of prostate cancer

SLEEP ◽  
2021 ◽  
Author(s):  
Xiaohui Sun ◽  
Ding Ye ◽  
Mengting Jiang ◽  
Yu Qian ◽  
Yingying Mao
Keyword(s):  
Prostate Cancer ◽  
Causal Effect ◽  
Association Studies ◽  
Meta Analysis ◽  
Prostate Cancer Risk ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Primary Analysis ◽  
Weighted Median ◽  
Reduced Risk

Abstract Study Objectives Observational epidemiological studies have suggested that chronotype may play a role in the pathogenesis and progression of prostate cancer. However, whether there is a causal association remains unknown. The aim of the present study was to examine the potential causal relationship between chronotype and prostate cancer risk using a Mendelian randomization (MR) design. Methods A total of 268 single nucleotide polymorphisms associated with chronotype were selected from a meta-analysis of genome-wide association studies of 697,828 individuals. The genetic association data for prostate cancer was derived from the Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome (PRACTICAL) Consortium (79,148 cases and 61,106 controls). Inverse-variance-weighted (IVW) method was used as the primary analysis to calculate the causal effect estimates. The weighted-median method, MR-Egger regression, MR-PRESSO test, and multivariable MR analyses were applied as sensitivity analysis. Results Genetically predicted morningness (scaled to a sleep midpoint of 1 hour earlier) had a reduced risk of prostate cancer, with an odds ratio of 0.71 (95% confidence interval (CI): 0.54-0.94 by IVW), compared with the eveningness. Similar causal effect estimates were also observed by using the weighted median and MR-PRESSO analyses. In addition, results from the multivariable MR analysis supported the findings from the univariable MR analyses. No indication of horizontal pleiotropy was observed in the MR-Egger analysis (P for intercept =0.234). Conclusion Our findings provide evidence of a causal protective effect of morning chronotype on the risk of prostate cancer.

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