CoBRA: Containerized Bioinformatics workflow for Reproducible ChIP/ATAC-seq Analysis - from differential peak calling to pathway analysis

Qiu, Xintao; Feit, Avery; Feiglin, Ariel; Xie, Yingtian; Kesten, Nikolas; Taing, Len; Perkins, Joseph; Zhou, Ningxuan; Gu, Shengqing Stan; Li, Yihao; Cejas, Paloma; Jeselsohn, Rinath; Brown, Myles; Liu, X. Shirley; Long, Henry W.

doi:10.1101/2020.11.06.367409

Cited by 4 publications

(4 citation statements)

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“…Sample-sample clustering, principal component analysis, and identification of lineage-enriched peaks were performed using Cobra v2.0 45 (https://bitbucket.org/ cfce/cobra/src/master/), a ChIP-seq analysis pipeline implemented with Snakemake 46 . ChIP-seq data from PRAD and NEPC LuCaP PDXs were compared to identify H3K27ac, H3K27me3, and FOXA1 peaks with significant enrichment in the NEPC or PRAD lineage.…”

Section: Identification and Annotation Of Prad-and Nepc-enriched Chipmentioning

confidence: 99%

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Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer

et al. 2021

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Lineage plasticity, the ability of a cell to alter its identity, is an increasingly common mechanism of adaptive resistance to targeted therapy in cancer. An archetypal example is the development of neuroendocrine prostate cancer (NEPC) after treatment of prostate adenocarcinoma (PRAD) with inhibitors of androgen signaling. NEPC is an aggressive variant of prostate cancer that aberrantly expresses genes characteristic of neuroendocrine (NE) tissues and no longer depends on androgens. Here, we investigate the epigenomic basis of this resistance mechanism by profiling histone modifications in NEPC and PRAD patient-derived xenografts (PDXs) using chromatin immunoprecipitation and sequencing (ChIP-seq). We identify a vast network of cis-regulatory elements (N~15,000) that are recurrently activated in NEPC. The FOXA1 transcription factor (TF), which pioneers androgen receptor (AR) chromatin binding in the prostate epithelium, is reprogrammed to NE-specific regulatory elements in NEPC. Despite loss of dependence upon AR, NEPC maintains FOXA1 expression and requires FOXA1 for proliferation and expression of NE lineage-defining genes. Ectopic expression of the NE lineage TFs ASCL1 and NKX2-1 in PRAD cells reprograms FOXA1 to bind to NE regulatory elements and induces enhancer activity as evidenced by histone modifications at these sites. Our data establish the importance of FOXA1 in NEPC and provide a principled approach to identifying cancer dependencies through epigenomic profiling.

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Section: Identification and Annotation Of Prad-and Nepc-enriched Chipmentioning

confidence: 99%

“…Code for the Cobra pipeline 45 used for the analyses in this paper is available at https:// bitbucket.org/cfce/cobra/src/master/.…”

Section: Data Availabilitymentioning

confidence: 99%

Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer

et al. 2021

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“…DNA binding motif analyses: Peaks from each group were used for motif analysis by the motif search findMotifsGenome.pl in HOMER (v3.0.0)31, with cutoff q-value ≤ 1e-10. Sample-sample correlation and differential peaks analysis: Sample-sample correlation and differential peaks analysis was performed by the CoBRA pipeline 66 . Peaks from all samples were merged to create a union set of sites for each transcription factor and histone mark.…”

Section: Bioinformatics Analyses -Chip-seqmentioning

confidence: 99%

MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets

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Hallal

et al. 2021

Preprint

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ABSTRACTc-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Importantly, analyses of clinical specimens revealed that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq revealed an increased RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.STATEMENT OF SIGNIFICANCEAR and MYC are key to prostate cancer etiology but our current understanding of their interplay is scarce. Here we show that the oncogenic transcription factor MYC can pause the transcriptional program of the master transcription factor in prostate cancer, AR, while turning on its own, even more lethal program.

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“…Downstream analyses depend on the biological context of the experiments and may consist of differential binding, motif analysis, and pathway analysis in the setting of chromatin profiling experiments. An independent Snakemake pipeline COBRA (Qiu et al 2020) is designed for this purpose.…”

Section: Discussionmentioning

confidence: 99%

CHIPS: A Snakemake pipeline for quality control and reproducible processing of chromatin profiling data

et al. 2021

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Motivation: The chromatin profile measured by ATAC-seq, ChIP-seq, or DNase-seq experiments can identify genomic regions critical in regulating gene expression and provide insights on biological processes such as diseases and development. However, quality control and processing chromatin profiling data involves many steps, and different bioinformatics tools are used at each step. It can be challenging to manage the analysis. Results: We developed a Snakemake pipeline called CHIPS (CHromatin enrIchment ProcesSor) to streamline the processing of ChIP-seq, ATAC-seq, and DNase-seq data. The pipeline supports single- and paired-end data and is flexible to start with FASTQ or BAM files. It includes basic steps such as read trimming, mapping, and peak calling. In addition, it calculates quality control metrics such as contamination profiles, polymerase chain reaction bottleneck coefficient, the fraction of reads in peaks, percentage of peaks overlapping with the union of public DNaseI hypersensitivity sites, and conservation profile of the peaks. For downstream analysis, it carries out peak annotations, motif finding, and regulatory potential calculation for all genes. The pipeline ensures that the processing is robust and reproducible. Availability: CHIPS is available at https://github.com/liulab-dfci/CHIPS.

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CoBRA: Containerized Bioinformatics workflow for Reproducible ChIP/ATAC-seq Analysis - from differential peak calling to pathway analysis

Cited by 4 publications

References 28 publications

Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer

Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer

MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets

CHIPS: A Snakemake pipeline for quality control and reproducible processing of chromatin profiling data

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