Analysis of chromatin accessibility uncovers TEAD1 as a regulator of migration in human glioblastoma.
Analysis of chromatin accessibility uncovers TEAD1 as a regulator of migration in human glioblastoma.
复制标题
DOI：
10.1038/s41467-018-06258-2
复制
发表时间：
2018-10-01
影响因子：
16.6
通讯作者：
Tsankova NM
中科院分区：
文献类型：
--
作者：
Tome-Garcia J;Erfani P;Nudelman G;Tsankov AM;Katsyv I;Tejero R;Bin Zhang;Walsh M;Friedel RH;Zaslavsky E;Tsankova NM
胶质母细胞瘤(GBM)迁移的内在驱动因素目前知之甚少。为了更好地捕捉GBM的天然分子印记及其发育背景，我们从GBM(GSC)和生发基质组织中分离出人类干细胞群体，并通过ATAC-SEQ绘制了它们的染色质可及性图。我们发现了两个不同的调控GSC信号，一个是发育共享/增殖的，另一个是肿瘤特异的/迁移的，其中TEAD1/4基序被独特地过度表达。利用芯片-聚合酶链式反应，我们验证了TEAD1在AQP4、EGFR和CDH4可及性部位的反式占有率。为了进一步表征TEAD在GBM中的功能作用，我们使用CRISPR-Cas9敲除了患者来源的GBM系中的TEAD1或TEAD4。TEAD1消融显著减少体外和体内的迁移，并改变迁移和EMT转录组特征，持续下调其靶标AQP4。TEAD1过表达可恢复AQP4的表达，TEAD1和AQP4过表达均可挽救TEAD1基因敲除细胞的迁移缺陷，提示TEAD1-AQP4在GBM迁移中起直接调节作用。胶质母细胞瘤(GBM)迁移的内在驱动因素仍然知之甚少。在这里，作者纯化了患者的GBM干细胞(GSCs)，并分析了这些细胞中染色质的可及性，确定TEAD1是人类胶质母细胞瘤中迁移的调节因子。
The intrinsic drivers of migration in glioblastoma (GBM) are poorly understood. To better capture the native molecular imprint of GBM and its developmental context, here we isolate human stem cell populations from GBM (GSC) and germinal matrix tissues and map their chromatin accessibility via ATAC-seq. We uncover two distinct regulatory GSC signatures, a developmentally shared/proliferative and a tumor-specific/migratory one in which TEAD1/4 motifs are uniquely overrepresented. Using ChIP-PCR, we validate TEAD1 trans occupancy at accessibility sites within AQP4, EGFR, and CDH4. To further characterize TEAD’s functional role in GBM, we knockout TEAD1 or TEAD4 in patient-derived GBM lines using CRISPR-Cas9. TEAD1 ablation robustly diminishes migration, both in vitro and in vivo, and alters migratory and EMT transcriptome signatures with consistent downregulation of its target AQP4. TEAD1 overexpression restores AQP4 expression, and both TEAD1 and AQP4 overexpression rescue migratory deficits in TEAD1-knockout cells, implicating a direct regulatory role for TEAD1–AQP4 in GBM migration. The intrinsic drivers of glioblastoma (GBM) migration are still poorly understood. Here the authors purify GBM stem cells (GSCs) from patients and profile chromatin accessibility in these cells, identifying TEAD1 as a regulator of migration in human glioblastoma.
登录
查看更多内容
影响因子：
11.2
作者：
Coma S;Amin DN;Shimizu A;Lasorella A;Iavarone A;Klagsbrun M
通讯作者：
Klagsbrun M
影响因子：
4.2
作者：
Gao, Yuan-Feng;Zhu, Tao;Liu, Zhao-Qian
通讯作者：
Liu, Zhao-Qian
影响因子：
50.3
作者：
Gallo, Marco;Coutinho, Fiona J.;Dirks, Peter B.
通讯作者：
Dirks, Peter B.
影响因子：
8
作者：
Bagci, T.;Wu, J. K.;Jay, D. G.
通讯作者：
Jay, D. G.
影响因子：
5.9
作者：
Carén H;Stricker SH;Bulstrode H;Gagrica S;Johnstone E;Bartlett TE;Feber A;Wilson G;Teschendorff AE;Bertone P;Beck S;Pollard SM
通讯作者：
Pollard SM