Super-enhancers for RUNX3 are required for cell proliferation in EBV-infected B cell lines.
Super-enhancers for RUNX3 are required for cell proliferation in EBV-infected B cell lines.
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DOI：
10.1016/j.gene.2021.145421
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发表时间：
2021-03-30
期刊：
影响因子：
3.5
通讯作者：
Osato M
中科院分区：
文献类型：
--
作者：
Hosoi H;Niibori-Nambu A;Nah GSS;Bahirvani AG;Mok MMH;Sanda T;Kumar AP;Tenen DG;Ito Y;Sonoki T;Osato M
EB病毒核抗原2（EBNA 2）介导的超级增强子，通过计算机数据定义，定位于与B细胞转录因子（包括RUNX 3）相关的基因附近。然而，RUNX 3基因的超级增强子（seR 3）的生物学功能尚不清楚。在此，我们发现两个串联位于RUNX 3转录起始位点上游59和70 kb的seR 3，命名为seR 3 - 59 h和seR 3 - 70 h，是EB病毒（EBV）阳性恶性B细胞中RUNX 3表达和细胞增殖所必需的。BET布罗莫结构域抑制剂JQ 1通过减少RUNX 3和MYC表达而有效抑制EBV阳性B细胞生长。通过使用CRISPR/Cas9系统切除任一个或两个seR 3导致RUNX 3表达的降低以及随后的细胞增殖和集落形成能力的抑制。当seR 3s缺失时，MYC的表达也降低，可能是由于seR 3s对MYC的超级增强子的反式作用丧失。这些发现表明，seR 3在RUNX 3和MYC的表达和生物学功能中起着关键作用。seR 3将作为EBV相关广泛性肿瘤的潜在治疗靶点。
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.
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影响因子：
64.8
作者：
Kwiatkowski, Nicholas;Zhang, Tinghu;Rahl, Peter B.;Abraham, Brian J.;Reddy, Jessica;Ficarro, Scott B.;Dastur, Anahita;Amzallag, Arnaud;Ramaswamy, Sridhar;Tesar, Bethany;Jenkins, Catherine E.;Hannett, Nancy M.;McMillin, Douglas;Sanda, Takaomi;Sim, Taebo;Kim, Nam Doo;Look, Thomas;Mitsiades, Constantine S.;Weng, Andrew P.;Brown, Jennifer R.;Benes, Cyril H.;Marto, Jarrod A.;Young, Richard A.;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.
人 T 细胞急性淋巴细胞白血病中由 TAL1 复合物控制的核心转录调节回路。
影响因子：
50.3
作者：
Sanda T;Lawton LN;Barrasa MI;Fan ZP;Kohlhammer H;Gutierrez A;Ma W;Tatarek J;Ahn Y;Kelliher MA;Jamieson CH;Staudt LM;Young RA;Look AT
通讯作者：
Look AT
DOI：
10.1073/pnas.91.16.7568
发表时间：
1994-08-02
影响因子：
11.1
作者：
GROSSMAN, SR;JOHANNSEN, E;KIEFF, E
通讯作者：
KIEFF, E
DOI：
10.1073/pnas.86.23.9558
发表时间：
1989-12-01
影响因子：
11.1
作者：
COHEN, JI;WANG, F;KIEFF, E
通讯作者：
KIEFF, E
影响因子：
8
作者：
Spender, LC;Whiteman, HJ;Farrell, PJ
通讯作者：
Farrell, PJ