STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1.

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Reports Pub Date : 2024-11-01 DOI:10.1038/s44319-024-00303-6

Daniel Giménez-Llorente, Ana Cuadrado, María José Andreu, Inmaculada Sanclemente-Alamán, Maria Solé-Ferran, Miriam Rodríguez-Corsino, Ana Losada

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Abstract

Cohesin complexes carrying STAG1 or STAG2 organize the genome into chromatin loops. STAG2 loss-of-function mutations promote metastasis in Ewing sarcoma, a pediatric cancer driven by the fusion transcription factor EWS::FLI1. We integrated transcriptomic data from patients and cellular models to identify a STAG2-dependent gene signature associated with worse prognosis. Subsequent genomic profiling and high-resolution chromatin interaction data from Capture Hi-C indicated that cohesin-STAG2 facilitates communication between EWS::FLI1-bound long GGAA repeats, presumably acting as neoenhancers, and their target promoters. Changes in CTCF-dependent chromatin contacts involving signature genes, unrelated to EWS::FLI1 binding, were also identified. STAG1 is unable to compensate for STAG2 loss and chromatin-bound cohesin is severely decreased, while levels of the processivity factor NIPBL remain unchanged, likely affecting DNA looping dynamics. These results illuminate how STAG2 loss modifies the chromatin interactome of Ewing sarcoma cells and provide a list of potential biomarkers and therapeutic targets.

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尤文肉瘤中 STAG2 的缺失会改变增强子-启动子接触，这种改变既依赖于 EWS::FLI1 也独立于 EWS::FLI1。

携带 STAG1 或 STAG2 的凝聚素复合物将基因组组织成染色质环。STAG2功能缺失突变可促进尤文肉瘤的转移，尤文肉瘤是一种由融合转录因子EWS::FLI1驱动的小儿癌症。我们整合了患者和细胞模型的转录组数据，确定了与预后恶化相关的 STAG2 依赖性基因特征。随后的基因组图谱分析和来自 Capture Hi-C 的高分辨率染色质相互作用数据表明，粘合素-STAG2 促进了 EWS::FLI1 结合的长 GGAA 重复序列（可能充当新增强子）与其目标启动子之间的交流。还发现了与 EWS::FLI1 结合无关的 CTCF 依赖性染色质接触的变化。STAG1 无法弥补 STAG2 的缺失，染色质结合的凝聚素严重减少，而加工因子 NIPBL 的水平保持不变，这可能会影响 DNA 循环动力学。这些结果阐明了STAG2缺失如何改变尤文肉瘤细胞的染色质相互作用组，并提供了潜在的生物标记物和治疗靶点列表。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.