Uniform, optimal signal processing of mapped deep-sequencing data

Kumar, Vibhor; Muratani, Masafumi; Rayan, Nirmala Arul; Kraus, Petra; Lufkin, Thomas; Ng, Huck Hui; Prabhakar, Shyam

doi:10.1038/nbt.2596

Cited by 153 publications

(138 citation statements)

References 52 publications

(75 reference statements)

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“…Two algorithms were used for peak calling of ERα ChIP-seq data: MACS 1.4 (22) and DFilter v1 (23). We used MACS with default parameter settings, except for the P value cutoff, which we set at 10 −7 .…”

Section: Methodsmentioning

confidence: 99%

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Droog

Nevedomskaya

Dackus

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The DNA-binding sites of estrogen receptor α (ERα) show great plasticity under the control of hormones and endocrine therapy. Tamoxifen is a widely applied therapy in breast cancer that affects ERα interactions with coregulators and shifts the DNA-binding signature of ERα upon prolonged exposure in breast cancer. Although tamoxifen inhibits the progression of breast cancer, it increases the risk of endometrial cancer in postmenopausal women. We therefore asked whether the DNA-binding signature of ERα differs between endometrial tumors that arise in the presence or absence of tamoxifen, indicating divergent enhancer activity for tumors that develop in different endocrine milieus. Using ChIP sequencing (ChIP-seq), we compared the ERα profiles of 10 endometrial tumors from tamoxifen users with those of six endometrial tumors from nonusers and integrated these results with the transcriptomic data of 47 endometrial tumors from tamoxifen users and 64 endometrial tumors from nonusers. The ERα-binding sites in tamoxifen-associated endometrial tumors differed from those in the tumors from nonusers and had distinct underlying DNA sequences and divergent enhancer activity as marked by histone 3 containing the acetylated lysine 27 (H3K27ac). Because tamoxifen acts as an agonist in the postmenopausal endometrium, similar to estrogen in the breast, we compared ERα sites in tamoxifen-associated endometrial cancers with publicly available ERα ChIP-seq data in breast tumors and found a striking resemblance in the ERα patterns of the two tissue types. Our study highlights the divergence between endometrial tumors that arise in different hormonal conditions and shows that ERα enhancer use in human cancer differs in the presence of nonphysiological endocrine stimuli.E strogen receptor α (ERα) is a steroid hormone receptor that behaves as a transcription factor by interacting with the DNA. The DNA-binding profile (cistrome) of ERα is dependent on context and tissue type (1). The hormonal environment of the cell greatly influences this cistrome because estrogen activates ERα by binding its ligand-binding domain. Upon activation, ERα's structural conformation changes to interact with cofactors at the DNA (2) and to regulate a transcriptional program that drives cell proliferation (3). Hence, the hormonal environment modulates the ERα cistrome and thereby rewires downstream effects.Endocrine therapies, as exemplified by tamoxifen, manipulate the DNA-binding capacities of the steroid hormone receptor ERα. Tamoxifen, a small-molecule inhibitor that competes with estrogens to bind ERα, is a major endocrine agent used in treating ERα-positive breast cancer patients. Studies in the breast cancer cell line MCF-7 show that prolonged tamoxifen exposure shifts the ERα cistrome, which consequently changes gene expression (4-6).Tamoxifen is a well-known selective estrogen receptor modulator (SERM) with tissue-selective physiological action. Early reports on tamoxifen's effects on transplanted MCF-7 cells in athymic mice revealed decreased tumor c...

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Section: Methodsmentioning

confidence: 99%

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Droog

Nevedomskaya

Dackus

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Reads were filtered based on MAPQ quality (reads with MAPQ>20) to eliminate reads from repetitive elements. Peak calling was performed over input, using Dfilter (27) and MACS peak caller version 1.4 (28). Only peaks identified using both algorithms were considered.…”

Section: Illumina Sequencing and Enrichment Analysismentioning

confidence: 99%

Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ERα in Tamoxifen-Associated Endometrial Carcinomas

et al. 2016

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Tamoxifen, a small-molecule antagonist of the transcription factor estrogen receptor alpha (ERa) used to treat breast cancer, increases risks of endometrial cancer. However, no parallels of ERa transcriptional action in breast and endometrial tumors have been found that might explain this effect. In this study, we addressed this issue with a genome-wide assessment of ERa-chromatin interactions in surgical specimens obtained from patients with tamoxifen-associated endometrial cancer. ERa was found at active enhancers in endometrial cancer cells as marked by the presence of RNA polymerase II and the histone marker H3K27Ac. These ERa binding sites were highly conserved between breast and endometrial cancer and enriched in binding motifs for the transcription factor FOXA1, which displayed substantial overlap with ERa binding sites proximal to genes involved in classical ERa target genes.Multifactorial ChIP-seq data integration from the endometrial cancer cell line Ishikawa illustrated a functional genomic network involving ERa and FOXA1 together with the enhancerenriched transcriptional regulators p300, FOXM1, TEAD4, FNFIC, CEBP8, and TCF12. Immunohistochemical analysis of 230 primary endometrial tumor specimens showed that lack of FOXA1 and ERa expression was associated with a longer interval between breast cancer and the emergence of endometrial cancer, exclusively in tamoxifen-treated patients. Our results define conserved sites for a genomic interplay between FOXA1 and ERa in breast cancer and tamoxifen-associated endometrial cancer. In addition, FOXA1 and ERa are associated with the interval time between breast cancer and endometrial cancer only in tamoxifen-treated breast cancer patients. Cancer Res; 76(13); 3773-84. Ó2016 AACR.

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“…org) using CLC assembly cell 4.2.0 with -c parameter for colorspace reads and -r to ignore redundant reads. Peak calling was performed using DFilter 1.0 with -std 2 (Kumar et al, 2013).…”

Section: Detection Of Dnase I Hypersensitive Sites and Histone Modifimentioning

confidence: 99%

Inference of Transcriptional Networks in Arabidopsis through Conserved Noncoding Sequence Analysis

2014

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Transcriptional regulation plays an important role in establishing gene expression profiles during development or in response to (a)biotic stimuli. Transcription factor binding sites (TFBSs) are the functional elements that determine transcriptional activity, and the identification of individual TFBS in genome sequences is a major goal to inferring regulatory networks. We have developed a phylogenetic footprinting approach for the identification of conserved noncoding sequences (CNSs) across 12 dicot plants. Whereas both alignment and non-alignment-based techniques were applied to identify functional motifs in a multispecies context, our method accounts for incomplete motif conservation as well as high sequence divergence between related species. We identified 69,361 footprints associated with 17,895 genes. Through the integration of known TFBS obtained from the literature and experimental studies, we used the CNSs to compile a gene regulatory network in Arabidopsis thaliana containing 40,758 interactions, of which two-thirds act through binding events located in DNase I hypersensitive sites. This network shows significant enrichment toward in vivo targets of known regulators, and its overall quality was confirmed using five different biological validation metrics. Finally, through the integration of detailed expression and function information, we demonstrate how static CNSs can be converted into condition-dependent regulatory networks, offering opportunities for regulatory gene annotation.

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Uniform, optimal signal processing of mapped deep-sequencing data

Cited by 153 publications

References 52 publications

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ERα in Tamoxifen-Associated Endometrial Carcinomas

Inference of Transcriptional Networks in Arabidopsis through Conserved Noncoding Sequence Analysis

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