文章：

EWSR1::ATF1融合基因在人类肿瘤及小鼠遗传模型中调控透明细胞肉瘤转录组

EWSR1::ATF1 Orchestrates the Clear Cell Sarcoma Transcriptome in Human Tumors and a Mouse Genetic Model

原文发布日期：8 December 2023

DOI: 10.3390/cancers15245750

类型: Article

开放获取: 是

英文摘要：

Clear cell sarcoma (CCS) is a rare, aggressive malignancy that most frequently arises in the soft tissues of the extremities. It is defined and driven by expression of one member of a family of related translocation-generated fusion oncogenes, the most common of which isEWSR1::ATF1. The EWSR1::ATF1 fusion oncoprotein reprograms transcription. However, the binding distribution of EWSR1::ATF1 across the genome and its target genes remain unclear. Here, we interrogated the genomic distribution of V5-tagged EWSR1::ATF1 in tumors it had induced upon expression in mice that also recapitulated the transcriptome of human CCS. ChIP-sequencing of V5-EWSR1::ATF1 identified previously unreported motifs including the AP1 motif and motif comprised of TGA repeats that resemble GGAA-repeating microsatellites bound by EWSR1::FLI1 in Ewing sarcoma. ChIP-sequencing of H3K27ac identified super enhancers in the mouse model and human contexts of CCS, which showed a shared super enhancer structure that associates with activated genes.

摘要翻译： 

透明细胞肉瘤是一种罕见的侵袭性恶性肿瘤，最常发生于四肢软组织。该肿瘤由一组易位融合癌基因家族中的某个成员表达所定义并驱动，其中最常见的是EWSR1::ATF1融合基因。EWSR1::ATF1融合癌蛋白能够重编程转录过程，但其在基因组中的结合分布及其靶基因仍不明确。本研究通过在小鼠模型中表达V5标记的EWSR1::ATF1诱导出再现人类透明细胞肉瘤转录组特征的肿瘤，进而探究了该融合蛋白的基因组分布。V5-EWSR1::ATF1的染色质免疫沉淀测序发现了此前未报道的基序，包括AP1基序和由TGA重复序列构成的基序，后者类似于尤文肉瘤中EWSR1::FLI1结合的GGAA重复微卫星序列。H3K27ac的染色质免疫沉淀测序在鼠模型及人类透明细胞肉瘤中均鉴定出超级增强子，这些增强子显示出与激活基因相关的共同超级增强子结构。

原文链接：

EWSR1::ATF1 Orchestrates the Clear Cell Sarcoma Transcriptome in Human Tumors and a Mouse Genetic Model