Dissecting the impact of regional identity and the oncogenic role of human-specific NOTCH2NL in an hESC model of H3.3G34R-mutant glioma.
Dissecting the impact of regional identity and the oncogenic role of human-specific NOTCH2NL in an hESC model of H3.3G34R-mutant glioma.
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DOI：
10.1016/j.stem.2021.02.003
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发表时间：
2021-05-06
期刊：
影响因子：
23.9
通讯作者：
Tabar V
中科院分区：
文献类型：
--
作者：
Funato K;Smith RC;Saito Y;Tabar V
H3.3G34R突变的胶质瘤是大脑半球的致命性肿瘤，其区域特异性和致瘤性机制尚不清楚。我们开发了一个基于人类胚胎干细胞的H3.3G34R突变胶质瘤模型，该模型概括了肿瘤的关键特征，具有对前脑神经元间祖细胞的细胞类型特异性，而不是后脑前体细胞。我们发现H3.3G34R、ATRX和TP53突变协同影响替代RNA剪接事件，特别是抑制内含子保留。这导致Notch途径的组成部分表达增加，特别是NOTCH2NL，一个人类特有的基因家族。我们还发现了在一些H3.3G34R突变的肿瘤中，通过基因组扩增NOTCH2NL基因表达增强的平行机制。这些发现表明了一种新的机制，通过这种机制，导致人类大脑更大的进化路径被选为驱动肿瘤生长的途径。Tabar和他的同事开发了H3.3G34R突变胶质瘤的人类胚胎干细胞模型。该模型将腹侧前脑神经元间祖细胞识别为假定的起源细胞，并揭示了替代的mRNA剪接和NOTCH2NL在肿瘤发生中的作用。
H3.3G34R-mutant gliomas are lethal tumors of the cerebral hemispheres, with unknown mechanisms of regional specificity and tumorigenicity. We developed a human embryonic stem cell-based model of H3.3G34R-mutant glioma that recapitulates the key features of the tumors, with cell type-specificity to forebrain interneuronal progenitors but not hindbrain precursors. We show that H3.3G34R, ATRX and TP53 mutations cooperatively impact alternative RNA splicing events, particularly suppression of intron retention. This leads to increased expression of components of the Notch pathway, notably NOTCH2NL, a human-specific gene family. We also uncover a parallel mechanism of enhanced NOTCH2NL expression via genomic amplification of its locus in some H3.3G34R-mutant tumors. These findings demonstrate a novel mechanism whereby evolutionary pathways that lead to larger brain size in humans are co-opted to drive tumor growth. A human embryonic stem cell model of H3.3G34R mutant gliomas was developed by Tabar and colleagues. The model identifies ventral forebrain interneuron progenitors as putative cells of origin and reveals a role for alternative mRNA splicing and NOTCH2NL in tumorigenesis.
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影响因子：
8
作者：
Imayoshi, Itaru;Shimojo, Hiromi;Sakamoto, Masayuki;Ohtsuka, Toshiyuki;Kageyama, Ryoichiro
通讯作者：
Kageyama, Ryoichiro
影响因子：
64.5
作者：
Goldberg AD;Banaszynski LA;Noh KM;Lewis PW;Elsaesser SJ;Stadler S;Dewell S;Law M;Guo X;Li X;Wen D;Chapgier A;DeKelver RC;Miller JC;Lee YL;Boydston EA;Holmes MC;Gregory PD;Greally JM;Rafii S;Yang C;Scambler PJ;Garrick D;Gibbons RJ;Higgs DR;Cristea IM;Urnov FD;Zheng D;Allis CD
通讯作者：
Allis CD
影响因子：
10.7
作者：
Lodewijk, Gerrald A.;Fernandes, Diana P.;Jacobs, Frank M. J.
通讯作者：
Jacobs, Frank M. J.
ATRX 缺失会促进肿瘤生长并损害神经胶质瘤中的非同源末端连接 DNA 修复。
影响因子：
17.1
作者：
Koschmann C;Calinescu AA;Nunez FJ;Mackay A;Fazal-Salom J;Thomas D;Mendez F;Kamran N;Dzaman M;Mulpuri L;Krasinkiewicz J;Doherty R;Lemons R;Brosnan-Cashman JA;Li Y;Roh S;Zhao L;Appelman H;Ferguson D;Gorbunova V;Meeker A;Jones C;Lowenstein PR;Castro MG
通讯作者：
Castro MG
影响因子：
30.8
作者：
Behjati, Sam;Tarpey, Patrick S.;Presneau, Nadege;Scheipl, Susanne;Pillay, Nischalan;Van Loo, Peter;Wedge, David C.;Cooke, Susanna L.;Gundem, Gunes;Davies, Helen;Nik-Zainal, Serena;Martin, Sancha;McLaren, Stuart;Goodie, Victoria;Robinson, Ben;Butler, Adam;Teague, Jon W.;Halai, Dina;Khatri, Bhavisha;Myklebost, Ola;Baumhoer, Daniel;Jundt, Gernot;Hamoudi, Rifat;Tirabosco, Roberto;Amary, M. Fernanda;Futreal, P. Andrew;Stratton, Michael R.;Campbell, Peter J.;Flanagan, Adrienne M.
通讯作者：
Flanagan, Adrienne M.