Functional interpretation of prostate cancer risk-associated SNPs
Ontology highlight
ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR359741.fastq.gz | Fastqsanger.gz | |||
| ERR359742.fastq.gz | Fastqsanger.gz | |||
| ERR359743.fastq.gz | Fastqsanger.gz | |||
| ERR359744.fastq.gz | Fastqsanger.gz | |||
| ERR359745.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 6 |
Similar Datasets
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
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 .
2015-07-10 | GSE70679 | GEO
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
Project description:Functional Significance of Prostate Cancer risk-SNPs
| PRJNA294704 | ENA
Project description:Differential susceptibility to recurrent infection and exacerbation in COPD is not well understood. Here we investigated the potential impact of genetic variation in Fatty Acid Binding Protein 5 (FABP5), a metabolic regulator we previously demonstrated to be downregulated in COPD and further downregulated in patients reporting one or more exacerbation. Through negative binomial analysis of the COPDGene SNP dataset, we identified 5 novel linked single nucleotide polymorphisms (SNPs) across the FABP5 locus that were significantly associated with severe exacerbations in a Non-Hispanic White cohort (rs4338057, rs12549270, rs202275, rs202277, and rs202279). We integrated multiple sources of previously published data to prioritize SNPs most likely to exert regulatory function. Ultimately, rs202275 emerged as the lead candidate due to unique alignment with the loading site of a bidirectional RNA Pol II signature of active enhancer utilization in our recently published patient-derived airway epithelial PRO-seq dataset, suggesting a critical regulatory role for the region harboring this variant. Using Micro-C genome-wide chromosome conformation capture, we found that the region harboring rs202275 makes three-dimensional physical contacts with the FABP5 transcription start site (TSS), suggesting the SNP region could regulate FABP5 transcription through a looping mechanism. To examine SNP function, we analyzed previously deposited gene-array data (GEO Accession #GSE42057) from peripheral blood mononuclear cell (PBMC) samples and found that COPD patients carrying the rs202275 risk allele (T) express significantly lower levels of FABP5 compared to non-carrier patients. Seahorse real-time mitochondrial respiration assays in freshly isolated PBMCs further revealed disrupted oxidative phosphorylation in cells from patients carrying the rs202275 risk allele. As macrophage polarization from pro-inflammatory toward pro-resolving phenotype is dependent on oxidative metabolism, the functional impact of the rs202275 risk allele and associated reduction in FABP5 transcription may contribute to increased or prolonged systemic inflammation, thereby increasing susceptibility to exacerbation in COPD.
2024-07-07 | GSE241294 | GEO
Project description:To understand the mechanistic role of HOXB13 lysine acetylation in CRPC development andd progression, differential gene expression analysis was performed following RNA-sequencing of the HOXB13K13A mutant versus the isogenic parental C4-2B to identify bonafide transcriptional targets of acetylated HOXB13. Chromatin remodeling and self-renewal genes were significantly impacted as a result of HOXB13-K13 mutation. These results suggested that single-site acetylation in HOXB13 is critical and may even be sufficient to promote cellular reprogramming associated with PC pathogenesis.
2022-09-22 | GSE174923 | GEO
Project description:In order to identify direct gene targets and pathways regulated by MEIS1 in prostate cells and identify mechanisms of observed tumor suppression with MEIS1 expression, we performed Chromatin Immunoprecipitation and sequencing (ChIP-seq) of MEIS1 in the CWR22Rv1-LV-MEIS1 line. Also, given the dependence of HOXB13, and to enable determination of HOXB13-dependent vs. HOXB13-independent MEIS1 DNA binding, we performed parallel MEIS1 ChIP-seq in the CWR22Rv1-HOXB13ko-LV-MEIS1 line. LV-MEIS1 denotes cells with exogenous lentiviral expression of MEIS1, and they still express endogenous HOXB13. Knockout of HOXB13 was achieved by CRISPR and validated with western blotting. HOXB13ko-LV-MEIS1 denotes cells where the same lentiviral expression of MEIS1 was infected into the HOXB13ko cells, so these cells are positive for MEIS1 expression and negative for HOXB13.
2020-07-15 | GSE132716 | GEO
Project description:We conducted RNA-sequencing to determine MEIS1-mediated gene regulation in prostate cancer cells because phenotypic data has demonstrated that expression of MEIS1 is sufficient to slow tumor growth and metastatic colonization in vitro and in vivo. These analyses compared global gene expression of CWR22Rv1-Control and CWR22Rv1-LV-MEIS1, as well as the HOXB13ko and HOXB13ko-LV-MEIS1 cells to precisely delineate MEIS1 and HOXB13-regulated genes. Importantly, inclusion of HOXB13ko lines enabled determination of HOXB13-associated gene regulation, as well as identification of significant changes between LV-MEIS1 vs. Control that are HOXB13-independent and thus unrelated to tumor suppression. Are samples are from CWR-22Rv1 cells. Control denotes cells with constitutive expression of Cas9, but with no gRNA provided. Control cells have nearly undetectable levels of endogenous MEIS1 expression, but do express HOXB13. LV-MEIS1 denotes cells with exogenous lentiviral expression of MEIS1, and they still express endogenous HOXB13. HOXB13ko denotes cells where HOXB13 was knocked out using CRISPR, 6 cell clones were isolated with confirmed HOXB13 knockout by western blot and pooled together into one line, so these cells lack both MEIS1 and HOXB13. HOXB13ko-LV-MEIS1 denotes cells where the same lentiviral expression of MEIS1 was infected into the HOXB13ko cell pool, so these cells are positive for MEIS1 expression and negative for HOXB13.
2020-07-15 | GSE132694 | GEO
Project description:Dysregulation of mTOR signaling plays a critical role in promoting prostate cancer (PCa) growth. HOXB13, a homeodomain transcription factor, is known to influence the androgen response and PCa development. Recently, HOXB13 was found to complex with mTOR on chromatin. However, the functional crosstalk between HOXB13 and mTOR remains elusive. We now report that mTOR directly interacts with and hierarchically phosphorylates HOXB13 at threonine 8 and 41 then serine 31 to promote its destabilization by the E3 ligase SKP2 while enhancing its oncogenic properties. Expression of HOXB13 harboring phosphomimetic mutations at the mTOR-targeted sites stimulates PCa cellular growth both in vitro and in murine xenografts. Transcriptional profiling studies revealed a phospho-HOXB13-dependent gene signature capable of robustly discriminating between normal prostate tissues, primary and metastatic PCa samples. This work uncovers a previously unanticipated molecular cascade by which mTOR directly phosphorylates HOXB13 to dictate a specific gene program with oncogenic implications in PCa.
2023-07-19 | GSE225206 | GEO
Project description:Skin biopsies were obtained from a patient with Mitchell-Riley syndrome caused by a homozygous frame-shift mutation (c.1129C>T) in the RFX6 gene that leads to a premature stop codon (p.Arg377X). The patient suffered severe pancreatic agenesis, in common with other Mitchell-Riley syndrome patients. Fibroblasts from the biopsy were reprogrammed to generate a human induced pluripotent stem cell (hiPSC) line (MRS2-6). To assess the effects of the mutant RFX6 allele on pancreas formation and identify direct targets of the transcription factor RFX6, MRS2-6 and H9 control human embryonic stem cells (hESC) were differentiated into pancreatic progenitors. Samples were harvested for RNA isolation and whole transcriptome analysis at days 4 (definitive endoderm), 7 and 8 (gut tube), and 12 (pancreatic progenitors).
2020-03-30 | E-MTAB-6626 | biostudies-arrayexpress