TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets.
TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets.
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DOI：
10.1038/s41467-018-06699-9
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发表时间：
2018-11-19
影响因子：
16.6
通讯作者：
Speleman F
中科院分区：
文献类型：
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作者：
Decaesteker B;Denecker G;Van Neste C;Dolman EM;Van Loocke W;Gartlgruber M;Nunes C;De Vloed F;Depuydt P;Verboom K;Rombaut D;Loontiens S;De Wyn J;Kholosy WM;Koopmans B;Essing AHW;Herrmann C;Dreidax D;Durinck K;Deforce D;Van Nieuwerburgh F;Henssen A;Versteeg R;Boeva V;Schleiermacher G;van Nes J;Mestdagh P;Vanhauwaert S;Schulte JH;Westermann F;Molenaar JJ;De Preter K;Speleman F
染色体17q的增加几乎总是出现在神经母细胞瘤的高危病例中。在这里，我们对H3K27ac定义的超级增强子标记的17q上的剂量敏感转录因子进行了整合的表观基因组学搜索，并确定TBX2为首选候选基因。我们发现，TBX2是最近在神经母细胞瘤中建立的核心调控电路的组成部分，具有细胞识别转录因子的特征，通过激活p21-Dream抑制的FOXM1靶基因来推动增殖。MYCN/TBX2联合敲除使细胞生长停止，表明TBX2增强了MYCN对FOXM1靶标的持续激活。CDK7和BET溴域联合抑制靶向转录成瘾对细胞活力有协同作用，对CRC基因表达和P53途径反应以及与转录调控有关的几个基因有很强的抑制作用。总之，我们对TBX2 CRC基因在神经母细胞瘤细胞转录依赖性中的作用提供了洞察力，为使用BET和CDK7抑制剂进行临床试验提供了依据。在神经母细胞瘤的高危病例中，染色体17q的增加是很常见的。在这里，作者研究了神经母细胞瘤的表观基因组学和转录组学，发现TBX2是一个核心调控电路组件，促进了MYCN/FOXM1对DREAM靶的重新激活。
Chromosome 17q gains are almost invariably present in high-risk neuroblastoma cases. Here, we perform an integrative epigenomics search for dosage-sensitive transcription factors on 17q marked by H3K27ac defined super-enhancers and identify TBX2 as top candidate gene. We show that TBX2 is a constituent of the recently established core regulatory circuitry in neuroblastoma with features of a cell identity transcription factor, driving proliferation through activation of p21-DREAM repressed FOXM1 target genes. Combined MYCN/TBX2 knockdown enforces cell growth arrest suggesting that TBX2 enhances MYCN sustained activation of FOXM1 targets. Targeting transcriptional addiction by combined CDK7 and BET bromodomain inhibition shows synergistic effects on cell viability with strong repressive effects on CRC gene expression and p53 pathway response as well as several genes implicated in transcriptional regulation. In conclusion, we provide insight into the role of the TBX2 CRC gene in transcriptional dependency of neuroblastoma cells warranting clinical trials using BET and CDK7 inhibitors. In high-risk neuroblastoma cases, gains in chromosome 17q are common. Here, the authors investigate the epigenomics and transcriptomics of neuroblastoma, identifying TBX2 as a core regulatory circuitry component enhancing the reactivation of DREAM targets by MYCN/FOXM1.