Super-enhancer-associated MEIS1 promotes transcriptional dysregulation in Ewing sarcoma in co-operation with EWS-FLI1

Lin, Lehang; Huang, Moli; Shi, Xianping; Mayakonda, Anand; Hu, Kaishun; Jiang, Yan‐Yi; Guo, Xiao; Chen, Li; Pang, Brendan; Doan, Ngan; Said, Jonathan; Xie, Jian‐Jun; Gery, Sigal; Xu, Chong‐Yu; Lin, Zhaoyu; Li, Jinsong; Berman, Benjamin P.; Ding, Yin; Lin, De–Chen; Koeffler, H. Phillip

doi:10.1093/nar/gky1207

Cited by 54 publications

(52 citation statements)

References 66 publications

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“…It could be speculated that CCAT1-L may regulate MYC expression by interacting with CTCF, which stabilizes long-range chromatin interactions of MYC promoter with MYC-335 or interaction of MYC-335 with MYC-515 [32]. Additionally, T-ALLrelated TAL1 [16], Ewing sarcoma-related MEIS1 [100], hepatocellular carcinoma (HCC)-correlated sphingosine kinase 1 (SPHK1) [101], HPV-induced E6 and E7 [61], oral squamous cell carcinoma (OSCC)-associated PAK4, RUNX1, DNAJB1, SREBF2 and YAP1 [102] are correspondingly regulated by oncogenic SE, and promote cancer development. and PD-L1 to inhibit immunity.…”

Section: Serna Promotes Oncogene Expressionmentioning

confidence: 99%

Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis

Tan

Tang

2020

Mol Cancer

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seRNA is a noncoding RNA (ncRNA) transcribed from active super-enhancer (SE), through which SE exerts biological functions and participates in various physiological and pathological processes. seRNA recruits cofactor, RNA polymerase II and mediator to constitute and stabilize chromatin loop SE and promoter region, which regulates target genes transcription. In tumorigenesis, DNA insertion, deletion, translocation, focal amplification and carcinogen factor mediate oncogenic SE generation, meanwhile, oncogenic SE transcribes into tumor-related seRNA, termed as oncogenic seRNA. Oncogenic seRNA participates in tumorigenesis through activating various signal-pathways. The recent reports showed that oncogenic seRNA implicates in a widespread range of cytopathological processes in cancer progression including cell proliferation, apoptosis, autophagy, epithelial-mesenchymal transition, extracellular matrix stiffness and angiogenesis. In this article, we comprehensively summarized seRNA's characteristics and functions, and emphatically introduced inducible formation of oncogenic seRNA and its functional mechanisms. Lastly, some research strategies on oncogenic seRNA were introduced, and the perspectives on cancer therapy that targets oncogenic seRNA were also discussed.

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Section: Serna Promotes Oncogene Expressionmentioning

confidence: 99%

Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis

Tan

Tang

2020

Mol Cancer

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“…In addition, like other central oncogenic transcription factors, such as MYC, MEIS1 has recently been linked to activation of a superenhancer (a region comprising multiple enhancers that bind several transcription factors, driving cell-identity transcription). In Ewing's sarcoma, MEIS1 is a super-enhancer-associated gene itself and cooperates with the EWS-FLI oncogene to activate the superenhancer of a cancer-associated downstream gene, linking MEIS protein activity to enhancer-mediated gene activation in cancer (Lin et al, 2019). Taken together, the examples described above show that RNA and protein levels can have limited predictive value for the functionality of TALE-HD transcription factors, which should be considered when evaluating expression data for MEIS or PBX genes in patient tumor samples.…”

Section: Versatile Roles Of Meis Proteins In Diseasementioning

confidence: 99%

MEIS transcription factors in development and disease

Schulte

Geerts

2019

Development

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MEIS transcription factors are key regulators of embryonic development and cancer. Research on MEIS genes in the embryo and in stem cell systems has revealed novel and surprising mechanisms by which these proteins control gene expression. This Primer summarizes recent findings about MEIS protein activity and regulation in development, and discusses new insights into the role of MEIS genes in disease, focusing on the pathogenesis of solid cancers.

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“…ChIP was performed using our previously-described methods with slight modifications (11, 63). 2x10 7 -2x10 8 of A673 cells were harvested and fixed with 1% paraformaldehyde for 10 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…ChIP-Seq was analyzed using established pipelines (11, 18). Raw reads were aligned to hg19 reference genome using bowtie 2 aligner (version 2.3.4.3) (64) followed by removal of PCR duplicates with Picard MarkDuplicates (http://broadinstitute.github.io/picard/).…”

Section: Methodsmentioning

confidence: 99%

“…Nevertheless, in many cases, EWS-FLI1 requires the cooperation of other transcriptional cofactors, such as WDR5 and CBP/p300, to regulate chromatin modification and gene expression (6–8). Moreover, EWS-FLI1-targeting transcription factors (TFs), such as MEIS1, NKX2-2, SOX2, and OTX2 (7, 9–11), are required for the fusion driver to fulfil its oncogenic function in Ewing sarcoma cells. Thus, despite having immense capacity in chromatin regulation, EWS-FLI1 still relies on additional cooperators and mediators to orchestrate gene expression programs in Ewing sarcoma.…”

Section: Introductionmentioning

confidence: 99%

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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-enhancer-associated MEIS1 promotes transcriptional dysregulation in Ewing sarcoma in co-operation with EWS-FLI1

Cited by 54 publications

References 66 publications

Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis

Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis

MEIS transcription factors in development and disease

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

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