Epigenetic regulators Rbbp4 and Hdac1 are overexpressed in a zebrafish model of RB1 embryonal brain tumor, and are required for neural progenitor survival and proliferation.
Epigenetic regulators Rbbp4 and Hdac1 are overexpressed in a zebrafish model of RB1 embryonal brain tumor, and are required for neural progenitor survival and proliferation.
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DOI：
10.1242/dmm.034124
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发表时间：
2018-06-15
影响因子：
4.3
通讯作者：
McGrail M
中科院分区：
文献类型：
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作者：
Schultz LE;Haltom JA;Almeida MP;Wierson WA;Solin SL;Weiss TJ;Helmer JA;Sandquist EJ;Shive HR;McGrail M
在这项研究中，我们使用比较基因组学和发育遗传学来确定在斑马鱼视网膜母细胞瘤1(Rb1)体细胞靶向RB1突变胚胎脑瘤模型中驱动肿瘤发生的表观遗传调控因子。由TALEN或CRISPR靶向引起的斑马鱼Rb1脑瘤在组织学上类似于人类中枢神经系统原始神经外胚层肿瘤(CNS-PNETs)。与人类少神经型OLIG2+/Sox10+CNS-PNET亚型一样，斑马鱼Rb1肿瘤表现出神经前体转录因子OLIG2、Sox10、Sox8b和受体酪氨酸激酶erb3a癌基因的高表达。Rb1肿瘤和Rb1/Rb1胚系突变幼虫转录本的比较表明，改变的寡神经前体特征是肿瘤组织所特有的。170多个染色质调节因子在Rb1肿瘤中差异表达，包括染色质重塑组份组蛋白脱乙酰基酶1(HDAC1)和视网膜母细胞瘤结合蛋白4(Rbbp4)的过度表达。生殖系突变分析证实，斑马鱼Rb1、Rbbp4和HDAC1是大脑发育所必需的。Rb1是神经前体细胞周期退出和终末分化所必需的，Rbbp4是有丝分裂后前体细胞生存所必需的，HDAC1维持神经干细胞/祖细胞库的增殖。我们提出了一种利用体细胞CRISPR靶向结合组蛋白-H_2A.F/Z-GFP融合蛋白在发育中的幼虫脑中的活体成像的方法，以快速测试染色质重构体在神经干细胞和祖细胞中的作用。我们的体细胞分析概括了生殖系突变的表型，并揭示了它们在神经细胞群体中的作用的动态观点。我们的研究为可能推动RB1脑瘤发病的表观遗传过程提供了新的见解，并确定Rbbp4及其相关的染色质重塑复合体是诱导RB1突变的脑癌细胞凋亡的潜在靶途径。摘要：这项研究表明，在RB1突变型脑癌的斑马鱼模型中过度表达的染色质重构体是神经前体细胞增殖和存活所必需的，这为深入了解驱动肿瘤生长的潜在机制提供了线索。
In this study, we used comparative genomics and developmental genetics to identify epigenetic regulators driving oncogenesis in a zebrafish retinoblastoma 1 (rb1) somatic-targeting model of RB1 mutant embryonal brain tumors. Zebrafish rb1 brain tumors caused by TALEN or CRISPR targeting are histologically similar to human central nervous system primitive neuroectodermal tumors (CNS-PNETs). Like the human oligoneural OLIG2+/SOX10+ CNS-PNET subtype, zebrafish rb1 tumors show elevated expression of neural progenitor transcription factors olig2, sox10, sox8b and the receptor tyrosine kinase erbb3a oncogene. Comparison of rb1 tumor and rb1/rb1 germline mutant larval transcriptomes shows that the altered oligoneural precursor signature is specific to tumor tissue. More than 170 chromatin regulators were differentially expressed in rb1 tumors, including overexpression of chromatin remodeler components histone deacetylase 1 (hdac1) and retinoblastoma binding protein 4 (rbbp4). Germline mutant analysis confirms that zebrafish rb1, rbbp4 and hdac1 are required during brain development. rb1 is necessary for neural precursor cell cycle exit and terminal differentiation, rbbp4 is required for survival of postmitotic precursors, and hdac1 maintains proliferation of the neural stem cell/progenitor pool. We present an in vivo assay using somatic CRISPR targeting plus live imaging of histone-H2A.F/Z-GFP fusion protein in developing larval brain to rapidly test the role of chromatin remodelers in neural stem and progenitor cells. Our somatic assay recapitulates germline mutant phenotypes and reveals a dynamic view of their roles in neural cell populations. Our study provides new insight into the epigenetic processes that might drive pathogenesis in RB1 brain tumors, and identifies Rbbp4 and its associated chromatin remodeling complexes as potential target pathways to induce apoptosis in RB1 mutant brain cancer cells. Summary: This study shows that chromatin remodelers that are overexpressed in a zebrafish model of RB1 mutant brain cancer are required for neural progenitor proliferation and survival, providing insight into potential mechanisms that drive tumor growth.
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影响因子：
3.7
作者：
Ignatius MS;Unal Eroglu A;Malireddy S;Gallagher G;Nambiar RM;Henion PD
通讯作者：
Henion PD
在发育，重编程和肿瘤发生过程中，视网膜的动态表观遗传景观。
影响因子：
16.2
作者：
Aldiri I;Xu B;Wang L;Chen X;Hiler D;Griffiths L;Valentine M;Shirinifard A;Thiagarajan S;Sablauer A;Barabas ME;Zhang J;Johnson D;Frase S;Zhou X;Easton J;Zhang J;Mardis ER;Wilson RK;Downing JR;Dyer MA;St. Jude Children’s Research Hospital—Washington University Pediatric Cancer Genome Project
通讯作者：
St. Jude Children’s Research Hospital—Washington University Pediatric Cancer Genome Project
影响因子：
--
作者：
Benavente CA;McEvoy JD;Finkelstein D;Wei L;Kang G;Wang YD;Neale G;Ragsdale S;Valentine V;Bahrami A;Temirov J;Pounds S;Zhang J;Dyer MA
通讯作者：
Dyer MA
影响因子：
--
作者：
Hayakawa T;Nakayama J
通讯作者：
Nakayama J
影响因子：
64.8
作者：
通讯作者：
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