HOXDeRNA activates a cancerous transcription program and super-enhancers genome-wide.
HOXDeRNA activates a cancerous transcription program and super-enhancers genome-wide.
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HOXDeRNA 激活癌性转录程序和全基因组超级增强子。
DOI：
10.1101/2023.06.30.547275
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Krichevsky,AnnaM
中科院分区：
文献类型：
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作者：
Deforzh,Evgeny;Kharel,Prakash;Karelin,Anton;Ivanov,Pavel;Krichevsky,AnnaM
研究背景恶性程度高的异质性胶质母细胞瘤的起源和发生机制尚不清楚。我们先前鉴定了一种增强子相关的长非编码RNA LINC 01116（此处命名为HOXDeRNA），其在正常脑中不存在，但通常在恶性胶质瘤中表达。HOXDeRNA具有将人类星形胶质细胞转化为神经胶质瘤样细胞的独特能力。这项工作的目的是调查潜在的分子事件的全基因组功能的lncRNA在神经胶质细胞的命运和transformation.ResultsUsing RNA-Seq，ChIRP-Seq，和ChIP-Seq的组合，我们现在证明，HOXDeRNA结合在反式的基因编码44个神经胶质瘤特异性转录因子分布在整个基因组的启动子，并通过删除Polycomb阻遏复合物2（PRC 2）去抑制它们。激活的转录因子包括核心神经发育调节因子SOX 2、OLIG 2、POU 3F 2和SALL 2。该过程需要HOXDeRNA的RNA四链体结构，其与EZH 2相互作用。此外，HOXDeRNA诱导的星形胶质细胞转化伴随着多种癌基因如EGFR、PDGFR、BRAF和miR-21的激活，以及胶质瘤特异性的超级增强子富集了胶质瘤主转录因子SOX 2和OLIG 2的结合位点。这些发现有助于重建星形胶质细胞转化过程中的事件序列，并表明HOXDeRNA的驱动作用和胶质瘤形成的统一RNA依赖机制。
BackgroundThe origin and genesis of highly malignant and heterogenous glioblastoma brain tumors remain unknown. We previously identified an enhancer-associated long non-coding RNA, LINC01116 (named HOXDeRNA here), that is absent in the normal brain but is commonly expressed in malignant glioma. HOXDeRNA has a unique capacity to transform human astrocytes into glioma-like cells. This work aimed to investigate molecular events underlying the genome-wide function of this lncRNA in glial cell fate and transformation.ResultsUsing a combination of RNA-Seq, ChIRP-Seq, and ChIP-Seq, we now demonstrate that HOXDeRNA binds in trans to the promoters of genes encoding 44 glioma-specific transcription factors distributed throughout the genome and derepresses them by removing the Polycomb repressive complex 2 (PRC2). Among the activated transcription factors are the core neurodevelopmental regulators SOX2, OLIG2, POU3F2, and SALL2. This process requires an RNA quadruplex structure of HOXDeRNA that interacts with EZH2. Moreover, HOXDeRNA-induced astrocyte transformation is accompanied by the activation of multiple oncogenes such as EGFR, PDGFR, BRAF, and miR-21, and glioma-specific super-enhancers enriched for binding sites of glioma master transcription factors SOX2 and OLIG2.ConclusionsOur results demonstrate that HOXDeRNA overrides PRC2 repression of glioma core regulatory circuitry with RNA quadruplex structure. These findings help reconstruct the sequence of events underlying the process of astrocyte transformation and suggest a driving role for HOXDeRNA and a unifying RNA-dependent mechanism of gliomagenesis.