Charting the prostate epigenomic landscape from transformation to progression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA540151 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11856200.fastq.gz | Fastqsanger.gz | |||
| SRR11856300.fastq.gz | Fastqsanger.gz | |||
| SRR11856400.fastq.gz | Fastqsanger.gz | |||
| SRR11856201.fastq.gz | Fastqsanger.gz | |||
| SRR11856301.fastq.gz | Fastqsanger.gz |
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Project description:Charting the prostate epigenomic landscape from transformation to progression
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Project description:To understand transcriptome and epigenome profilings alteration during breast cancer initiation and development, we constructed a in vitro breast cancer transformation model. And then, we use mRNA-Seq to uncover differential expression genes during breast cancer transformation process. For epigenomic profilings, we specificly analysis genome wide H3K9me2, H3K9me3,H3K4me3 and H3K27me3 modifications using ChIP-Seq. We found that H3K9 di and tri methylation decrease both in vitro breast cancer cell transformation model and in vivo clinical samples. Further more, we found KDM3A, a demethylase for H3K9 mono and di methylation, increase during the breast cancer model transformation process and clinical samples. KDM3A deficiency impairs the growth of those transformed cell lines and its overexpression promotes tumor formation.
2016-04-08 | GSE64367 | GEO
Project description:Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions-from normal prostate epithelium to localized PCa to metastases-in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa are not created de novo; rather, they are prepopulated by the transcription factors FOXA1 and HOXB13 in normal prostate epithelium. Reprogrammed regulatory elements commissioned in metastatic disease hijack latent developmental programs, accessing sites that are implicated in prostate organogenesis. Analysis of reactivated regulatory elements enabled the identification and functional validation of previously unknown metastasis-specific enhancers at HOXB13, FOXA1 and NKX3-1. Finally, we observed that prostate lineage-specific regulatory elements were strongly associated with PCa risk heritability and somatic mutation density. Examining prostate biology through an epigenomic lens is fundamental for understanding the mechanisms underlying tumor progression.
| S-EPMC10007911 | biostudies-literature
Project description:The Epigenomic Landscape of Prokaryotes
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Project description:BackgroundMajority of prostate cancer (PCa) deaths are attributed to localized high-grade aggressive tumours which progress rapidly to metastatic disease. A critical unmet need in clinical management of PCa is discovery and characterization of the molecular drivers of aggressive tumours. The development and progression of aggressive PCa involve genetic and epigenetic alterations occurring in the germline, somatic (tumour), and epigenomes. To date, interactions between genes containing germline, somatic, and epigenetic mutations in aggressive PCa have not been characterized. The objective of this investigation was to elucidate the genomic-epigenomic interaction landscape in aggressive PCa to identify potential drivers aggressive PCa and the pathways they control. We hypothesized that aggressive PCa originates from a complex interplay between genomic (both germline and somatic mutations) and epigenomic alterations. We further hypothesized that these complex arrays of interacting genomic and epigenomic factors affect gene expression, molecular networks, and signaling pathways which in turn drive aggressive PCa.MethodsWe addressed these hypotheses by performing integrative data analysis combining information on germline mutations from genome-wide association studies with somatic and epigenetic mutations from The Cancer Genome Atlas using gene expression as the intermediate phenotype.ResultsThe investigation revealed signatures of genes containing germline, somatic, and epigenetic mutations associated with aggressive PCa. Aberrant DNA methylation had effect on gene expression. In addition, the investigation revealed molecular networks and signalling pathways enriched for germline, somatic, and epigenetic mutations including the STAT3, PTEN, PCa, ATM, AR, and P53 signalling pathways implicated in aggressive PCa.ConclusionsThe study demonstrated that integrative analysis combining diverse omics data is a powerful approach for the discovery of potential clinically actionable biomarkers, therapeutic targets, and elucidation of oncogenic interactions between genomic and epigenomic alterations in aggressive PCa.
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Project description:Charting the regulatory landscape of TP53 on transposable elements in cancer [WGBS]
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Project description:Background: Follicular lymphoma (FL) is an indolent, yet incurable B-cell malignancy. A subset of patients experience increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immuno-chemotherapy. The nature of tumor clonal dynamics leading to these clinical endpoints is poorly understood and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the timecourse of FL clinical histories.
Methods and Findings: Using a combination of whole genome sequencing, targeted deep sequencing and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in n=15 transformation patients and n=6 progressors, and measured their change in abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimen. This pattern was independent of time to transformation and treatment modality. By contrast, progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immuno-chemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in a validation cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical endpoints. We found 12 genes were more commonly mutated in transformed samples than in preceding FL, including TP53, B2M, CCND3, GNA13, S1PR2 and P2RY8. Moreover, 10 genes were more commonly mutated in diagnostic specimens of early progressors including TP53, BTG1, MKI67 and XBP1.
Conclusions: Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implication for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.
| EGAS00001001709 | EGA