Bromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma

Chen, Ye; Xu, Lu; Mayakonda, Anand; Huang, Moli; Kanojia, Deepika; Tan, Tuan Zea; Dakle, Pushkar; Lin, Ruby Yu-Tong; Ke, Xin-Yu; Said, Jonathan; Chen, Jianxiang; Gery, Sigal; Ding, Ling-Wen; Jiang, Yan‐Yi; Pang, Angela; Puhaindran, Mark E.; Goh, Boon Cher; Koeffler, H. Phillip

doi:10.1038/s41467-019-09257-z

Cited by 43 publications

(69 citation statements)

References 66 publications

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“…This involves performing ChIP-seq experiments to map enhancers and identifying SE associated TFs whose predicted binding motifs are enriched at SEs, both upstream and regulating other MTFs . These approaches have been shown to recover experimentally validated MTFs in various tumor types (Chen et al, 2019a(Chen et al, , 2019bLin et al, 2016;Ott et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Predicting master transcription factors from pan-cancer expression data

Reddy

Fonseca

Fuente

et al. 2019

Preprint

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The function of critical developmental regulators can be subverted by cancer cells to control expression of oncogenic transcriptional programs. These "master transcription factors" (MTFs) are often essential for cancer cell survival and represent vulnerabilities that can be exploited therapeutically. The current approaches to identify candidate MTFs examine super-enhancer associated transcription factor-encoding genes with high connectivity in network models. This relies on chromatin immunoprecipitation-sequencing (ChIP-seq) data, which is technically challenging to obtain from primary tumors, and is currently unavailable for many cancer types and clinically relevant subtypes. In contrast, gene expression data are more widely available, especially for rare tumors and subtypes where MTFs have yet to be discovered. We have developed a predictive algorithm called CaCTS (Cancer Core Transcription factor Specificity) to identify candidate MTFs using pancancer RNA-sequencing data from The Cancer Genome Atlas. The algorithm identified 273 candidate MTFs across 34 tumor types and recovered known tumor MTFs. We also made novel predictions, including for cancer types and subtypes for which MTFs have not yet been characterized. Clustering based on MTF predictions reproduced anatomic groupings of tumors that share 1-2 lineage-specific candidates, but also dictated functional groupings, such as a squamous group that comprised five tumor subtypes sharing 3 common MTFs. PAX8, SOX17, and MECOM were candidate factors in high-grade serous ovarian cancer (HGSOC), an aggressive tumor type where the core regulatory circuit is currently uncharacterized. PAX8, SOX17, and MECOM are required for cell viability and lie proximal to super-enhancers in HGSOC cells. ChIPseq revealed that these factors co-occupy HGSOC regulatory elements globally and co-bind at critical gene loci including MUC16 (CA-125). Addiction to these factors was confirmed in studies using THZ1 to inhibit transcription in HGSOC cells, suggesting early down-regulation of these genes may be responsible for cytotoxic effects of THZ1 on HGSOC models. Identification of MTFs across 34 tumor types and 140 subtypes, especially for those with limited understanding of transcriptional drivers paves the way to therapeutic targeting of MTFs in a broad spectrum of cancers.

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Section: Introductionmentioning

confidence: 99%

Predicting master transcription factors from pan-cancer expression data

Reddy

Fonseca

Fuente

et al. 2019

Preprint

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“…As introduced earlier, considering that CRC is particularly important for childhood developmental cancers having few genomic lesions, we postulated that such CRC model might also contribute to regulating Ewing sarcoma transcriptome through either cooperating with or mediating the function of EWS-FLI1. To test this hypothesis, we first sought to identify mathematically master TFs with high inter-connectivity through binding to their super-enhancers by motif scanning using our established method (18, 24, 25). Because of the central role of EWS-FLI1 in establishing the enhancer landscape in Ewing sarcoma, we made significant modifications of the method by requiring that all candidate TFs have both EWS-FLI1 binding motif and binding peaks in their assigned super-enhancers.…”

Section: Resultsmentioning

confidence: 99%

“…CRC was computationally constructed using our published methodology (18, 24, 25) with important modifications. Given the central role of EWS-FLI1 in establishing the transcriptome of Ewing Sarcoma cells, we required that all candidate CRC members have both EWS-FLI1 binding motif and binding peaks in their super-enhancer regions.…”

Section: Methodsmentioning

confidence: 99%

EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma

Shi

Zheng

Jiang

et al. 2020

Preprint

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29Core regulatory circuitry (CRC)-dependent transcriptional network is critical for 30 developmental tumors in children and young adults carrying few gene mutations. 31 Ewing sarcoma resembles these developmental cancers in terms of having both 87 few genomic alterations and a single epigenomic driver, we postulated that such 88 oncogenic CRC model might exist in Ewing sarcoma, to cooperate with the 89 transcriptional function of EWS-FLI1. The current study was aimed to identify 90 and characterize this CRC apparatus in Ewing sarcoma, and to elucidate its 91 functional significance in this cancer. 92 93 94 5 / 46 Results 95 96 We recently characterized the super-enhancer landscape in Ewing sarcoma and 97 confirmed the essential role of EWS-FLI1 in regulating the epigenome of this 98 cancer (11). As introduced earlier, considering that CRC is particularly important 99 for childhood developmental cancers having few genomic lesions, we postulated 100 that such CRC model might also contribute to regulating Ewing sarcoma 101 transcriptome through either cooperating with or mediating the function of EWS-102 FLI1. To test this hypothesis, we first sought to identify mathematically master 103 TFs with high inter-connectivity through binding to their super-enhancers by 104 motif scanning using our established method (18, 24, 25). Because of the central 105 role of EWS-FLI1 in establishing the enhancer landscape in Ewing sarcoma, we 106 made significant modifications of the method by requiring that all candidate TFs 107 have both EWS-FLI1 binding motif and binding peaks in their assigned super-108 enhancers. We initially focused on the A673 cell line, since it is a well-109 characterized Ewing sarcoma line with available H3K27ac and EWS-FLI1 ChIP-110 Seq results (7). As a result, a small set (n=9) of CRC candidates were identified 111 (Fig. 1A), including NKX2-2 and FOS which are known functional cooperators 112 of EWS-FLI1 (7, 26). Because CRC factors have high and specific expression in 113 their corresponding cell types, we interrogated the Cancer Cell Line Encyclopedia 114 (CCLE) dataset and noted that, compared with other 5 CRC candidates (NFATC2, 115 FOS, IRF2, ZBTB7B and MEF2D, Supplement Fig. 1), the expression of 4 116 6 / 46 candidate TFs (KLF15, NKX2-2, TCF4 and RREB1) showed restricted 117 expression pattern in Ewing sarcoma cell lines (defined as top 5 among all cell 118 types, Fig. 1B). However, it should be noted that the specificity of RREB1 119 expression was overall poor, as most cancer types had comparable mRNA levels. Identification of CRC under the regulation of EWS-FLI1 in Ewing sarcoma 120As a parallel analysis, Pearson correlation coefficient of the mRNA levels of 121 these 9 candidates was determined, considering the co-regulatory relationship 122 between CRC members. Notably, the same set of 4 factors (KLF15, NKX2-2, 123 TCF4 and RREB1) displayed strong positive correlations with each other (Fig. 124 1C). In contrast, this correlation pattern was much weaker in other non-Ewing 125 sarco...

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“…Super-enhancers exert a major role in the progression of various tumor types including PCa (Baumgart et al, 2019;He et al, 2019;Zuber et al, 2017) and also contribute to resistance mechanisms involving SEbinding factors such as BRD4 or FOXP1 (Bao et al, 2019;Chen et al, 2019;Natsume et al, 2019). SE regions have been identified in PCa models but the associated genes and the impact of AR antagonists have not been dissected.…”

Section: Discussionmentioning

confidence: 99%

Darolutamide antagonizes androgen signaling by blocking enhancer and super‐enhancer activation

et al. 2020

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Prostate cancer (PCa) is one of the most frequent tumor types in the male Western population. Early-stage PCa and late-stage PCa are dependent on androgen signaling, and inhibitors of the androgen receptor (AR) axis represent the standard therapy. Here, we studied in detail the global impact of darolutamide, a newly approved AR antagonist, on the transcriptome and AR-bound cistrome in two PCa cell models. Darolutamide strongly depleted the AR from gene regulatory regions and abolished AR-driven transcriptional signaling. Enhancer activation was blocked at the chromatin level as evaluated by H3K27 acetylation (H3K27ac), H3K4 monomethylation (H3K4me1), and FOXA1, MED1, and BRD4 binding. We identified genomic regions with high affinities for the AR in androgen-stimulated, but also in androgen-depleted conditions. A similar AR affinity pattern was observed in healthy and PCa tissue samples. High FOXA1, BRD4, H3K27ac, and H3K4me1 levels were found to mark regions showing AR binding in the hormone-depleted setting. Conversely, low FOXA1, BRD4, and H3K27ac levels were observed at regulatory sites that responded strongly to androgen stimulation, and AR interactions at these sites were blocked by darolutamide. Beside marked loss of AR occupancy, FOXA1 recruitment to chromatin was also clearly reduced after darolutamide treatment. We furthermore identified numerous androgen-regulated super-enhancers (SEs) that were associated with hallmark androgen and cell proliferation-associated gene sets. Importantly, these SEs are also active in PCa tissues and sensitive to darolutamide treatment in our models. Our findings demonstrate that darolutamide is a potent AR antagonist blocking genome-wide AR enhancer and SE activation, and downstream transcription. We also show the existence of a dynamic AR cistrome that depends on the androgen levels and on high AR affinity regions present in PCa cell lines and also in tissue samples.

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Bromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma

Cited by 43 publications

References 66 publications

Predicting master transcription factors from pan-cancer expression data

Predicting master transcription factors from pan-cancer expression data

EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma

Darolutamide antagonizes androgen signaling by blocking enhancer and super‐enhancer activation

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