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Super-enhancers for RUNX3 are required for cell proliferation in EBV-infected B cell lines
Gene ( IF 3.5 ) Pub Date : 2021-01-12 , DOI: 10.1016/j.gene.2021.145421
Hiroki Hosoi 1 , Akiko Niibori-Nambu 2 , Giselle Sek Suan Nah 3 , Avinash Govind Bahirvani 3 , Michelle Meng Huang Mok 3 , Takaomi Sanda 4 , Alan Prem Kumar 5 , Daniel G Tenen 6 , Yoshiaki Ito 3 , Takashi Sonoki 7 , Motomi Osato 8
Affiliation  

Epstein-Barr virus nuclear antigens 2 (EBNA2) mediated super-enhancers, defined by in silico data, localize near genes associated with B cell transcription factors including RUNX3. However, the biological function of super-enhancer for RUNX3 gene (seR3) remains unclear. Here, we show that two seR3s, tandemly-located at 59- and 70-kb upstream of RUNX3 transcription start site, named seR3 −59h and seR3 −70h, are required for RUNX3 expression and cell proliferation in Epstein-Barr virus (EBV)-positive malignant B cells. A BET bromodomain inhibitor, JQ1, potently suppressed EBV-positive B cell growth through the reduction of RUNX3 and MYC expression. Excision of either or both seR3s by employing CRISPR/Cas9 system resulted in the decrease in RUNX3 expression and the subsequent suppression of cell proliferation and colony forming capability. The expression of MYC was also reduced when seR3s were deleted, probably due to the loss of trans effect of seR3s on the super-enhancers for MYC. These findings suggest that seR3s play a pivotal role in expression and biological function of both RUNX3 and MYC. seR3s would serve as a potential therapeutic target in EBV-related widespread tumors.



中文翻译:

在EBV感染的B细胞系中,细胞增殖需要RUNX3超级增强剂

爱泼斯坦巴尔病毒核抗原2(EBNA2)介导的超级增强子,由计算机模拟数据定义,位于与B细胞转录因子(包括RUNX3)相关的附近基因。但是,尚不清楚RUNX3基因(seR3)的超级增强剂的生物学功能。在这里,我们显示了两个seR3,分别位于RUNX3转录起始位点上游59-和70-kb ,名为seR3-59h和seR3-70h,是RUNX3表达和爱泼斯坦-巴尔病毒(EBV)细胞增殖所必需的阳性恶性B细胞。BET溴结构域抑制剂JQ1通过降低RUNX3MYC来有效抑制EBV阳性B细胞生长表达。通过使用CRISPR / Cas9系统切除一个或两个seR3,会导致RUNX3表达下降,并随后抑制细胞增殖和集落形成能力。当缺失seR3时,MYC的表达也降低了,这可能是由于seR3对MYC的超级增强子的反式作用丧失了。这些发现表明,seR3在RUNX3MYC的表达和生物学功能中均起着关键作用。seR3s将作为与EBV相关的广泛肿瘤的潜在治疗靶标。

更新日期:2021-01-22
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