Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA386902 | ENA |
REPOSITORIES: ENA
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Project description:Prostate cancer (PCa) is the leading cancer among men in the United States, with genetic factors contributing to ~42% of the susceptibility to PCa. To understand the causal genetic factors associated with PCa, we have focused on a PCa risk region located at 7p15.2. We performed Hi-C analysis and demonstrated that this region has long range interactions with the HOXA locus, located ~873 kb away. Using the CRISPR/Cas9 system, we deleted a 4 kb region encompassing several prostate cancer risk-associated SNPs and performed RNA-seq to investigate transcriptomic changes in RWPE1 prostate cells lacking the regulatory element. Our results suggest that the risk element affects the expression of HOXA13 and HOTTIP, but not other genes in the HOXA locus, via a repressive loop. Forced expression of HOXA13 was also performed to gain insight into the mechanisms by which this risk element affects prostate cancer risk.
2017-11-01 | GSE98898 | GEO
Project description:CRISPR-mediated deletion of prostate cancer risk-associated CTCF loop anchors identifies repressive chromatin loops
| PRJNA485892 | ENA
Project description:Functional Significance of Prostate Cancer risk-SNPs
| PRJNA294705 | ENA
Project description:Vitamin D induces anti-proliferative and differentiating effects in prostate cancer. Thus calcitriol, the hormonally active form of Vitamin D, and its analogs have been extensively studied in prostate cancer cells. Yet despite its importance, relatively little is known about the genome-scale mechanisms by which Vitamin D, through its cognate nuclear vitamin D receptor (VDR), exerts its regulatory functions at the genomic level. In this study, we defined VDR transcriptional networks in the LNCaP prostate cancer cell line by mapping the genomic binding sites of VDR and by identifying differentially expressed genes upon calcitriol treatment. We found that VDR and androgen receptor (AR) antagonistically regulate a subset of cell cycle-related genes that are over-expressed in prostate cancer tumors. The expression balance of these genes is partially regulated through the competition dynamics between AR and VDR binding to shared cis-regulatory elements. On such shared elements, we found that FOXA1 mediates this competition by serving as a pioneering factor for both AR and VDR binding. We also found significant enrichment of AR-, VDR-, and AR/VDR overlapping binding sites in prostate cancer-associated single-nucleotide polymorphism (SNP) intervals identified from genome-wide association studies (GWAS), providing genetic evidence to link AR, VDR and their crosstalk to prostate cancer susceptibilities. In particular, we found that in a cis-regulatory element of the RFX6 gene implicated in prostate cancer progression, an allelic variant increases prostate cancer risk by switching the antagonism between AR and VDR into a synergistic interaction. Examination of AR, VDR, and FOXA1 binding in LNCaP cells, in biological replicates
2015-08-01 | E-GEOD-64656 | biostudies-arrayexpress
Project description:Genome-wide association studies (GWAS) have revolutionized the field of cancer genetics, but the causal links between increased genetic risk and onset/progression of disease processes remain to be identified. Here we report the first step in such an endeavor for prostate cancer. We provide a comprehensive annotation of the 77 known risk loci, based upon highly correlated variants in biologically relevant chromatin annotations- we identified 727 such potentially functional SNPs. We also provide a detailed account of possible protein disruption, microRNA target sequence disruption and regulatory response element disruption of all correlated SNPs at r^2≥0.5. Greater than 88% of the 727 SNPs fall within putative enhancers, many of which alter critical residues in the response elements of transcription factors known to be involved in prostate biology. We define as risk enhancers those regions with enhancer chromatin biofeatures in prostate-derived cell lines with prostate-cancer correlated SNPs. To aid in the identification of these enhancers, we performed genomewide ChIP-seq for H3K27-acetylation, a mark of actively engaged enhancer regions, as well as the transcription factor TCF7L2. We analyzed in depth three variants in risk enhancers, two of which show significantly altered androgen sensitivity in LNCaP cells. This includes rs4907792, that is in linkage disequilibrium (r^2=0.91) with an eQTL for NUDT11 (on the X chromosome) in prostate tissue, and rs10486567, the index SNP in intron 3 of the JAZF1 gene on chromosome 7. Rs4907792 is within a critical residue of a strong consensus androgen response element that is interrupted in the protective allele, resulting in a 56% decrease in its androgen sensitivity, whereas rs10486567 affects both NKX3-1 and FOXA-AR motifs where the risk allele results in a 39% increase in basal activity and a 28% fold-increase in androgen stimulated enhancer activity. Identification of such enhancer variants and their potential target genes represents a preliminary step in connecting risk to disease process. ChIP-seq analysis of H3K27Ac in LNCaP charcoal-stripped serum, H3K27Ac in LNCaP charcoal-stripped serum +DHT, TCF7L2 in LNCaP
2014-01-28 | E-GEOD-51621 | biostudies-arrayexpress
Project description:ERK signaling regulates opposing functions of JUN family transcription factors in prostate cancer cell migration
| PRJNA232070 | ENA
Project description:Vitamin D induces anti-proliferative and differentiating effects in prostate cancer. Thus calcitriol, the hormonally active form of Vitamin D, and its analogs have been extensively studied in prostate cancer cells. Yet despite its importance, relatively little is known about the genome-scale mechanisms by which Vitamin D, through its cognate nuclear vitamin D receptor (VDR), exerts its regulatory functions at the genomic level. In this study, we defined VDR transcriptional networks in the LNCaP prostate cancer cell line by mapping the genomic binding sites of VDR and by identifying differentially expressed genes upon calcitriol treatment. We found that VDR and androgen receptor (AR) antagonistically regulate a subset of cell cycle-related genes that are over-expressed in prostate cancer tumors. The expression balance of these genes is partially regulated through the competition dynamics between AR and VDR binding to shared cis-regulatory elements. On such shared elements, we found that FOXA1 mediates this competition by serving as a pioneering factor for both AR and VDR binding. We also found significant enrichment of AR-, VDR-, and AR/VDR overlapping binding sites in prostate cancer-associated single-nucleotide polymorphism (SNP) intervals identified from genome-wide association studies (GWAS), providing genetic evidence to link AR, VDR and their crosstalk to prostate cancer susceptibilities. In particular, we found that in a cis-regulatory element of the RFX6 gene implicated in prostate cancer progression, an allelic variant increases prostate cancer risk by switching the antagonism between AR and VDR into a synergistic interaction. Gene expression profiling in LNCaP cells after 24hr treatment with different nuclear recpetor ligrands, with time-matching control, in triplicates Expression is assayed with Agilent G4112F.
2015-08-01 | E-GEOD-60956 | biostudies-arrayexpress
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
Project description:We adapted the DiR barcode-based parallel reporter assay systems strategy to systematically identify the SNPs that affect gene expression by modulating activities of regulatory elements. Among 293 SNPs linked with GWAS-identified prostate cancer-risk SNPs, we found 32, 9, and 11 regulatory SNPs in 22Rv1, PC-3, and LNCaP cells. Further mechanism study indicates that one SNP regulates gene expression in prostate cancer malignancy. The DiR system has great potential to advance the functional study of risk SNPs that have associations with polygenic diseases. Our findings hold great promise in benefiting prostate cancer patients with prognostic prediction.
2021-01-30 | GSE165765 | GEO
Project description:Comprehensive Functional Annotation of 77 Prostate Cancer Risk Loci
| PRJNA224101 | ENA