Far Upstream Element-Binding Protein 1 Regulates LSD1 Alternative Splicing to Promote Terminal Differentiation of Neural Progenitors.
Far Upstream Element-Binding Protein 1 Regulates LSD1 Alternative Splicing to Promote Terminal Differentiation of Neural Progenitors.
复制标题
DOI：
10.1016/j.stemcr.2018.02.013
复制
发表时间：
2018-04-10
影响因子：
5.9
通讯作者：
Paik J
中科院分区：
文献类型：
--
作者：
Hwang I;Cao D;Na Y;Kim DY;Zhang T;Yao J;Oh H;Hu J;Zheng H;Yao Y;Paik J
由于突变而导致细胞最终分化能力的丧失是肿瘤发生中的选择性遗传事件。低级别胶质瘤的基因组分析报告了远上游元件结合蛋白 1 (FUBP1) 的反复突变。在这里，我们发现 FUBP1 的表达在神经发生过程中受到动态调节，并且其在神经祖细胞中的下调会损害终末分化，并与 IDH1R132H 的表达协同促进肿瘤发生。从机制上讲，SRRM4 和 FUBP1 之间的协同作用对于神经特异性 LSD1+8a 亚型的迷你外显子剪接是必要的。当神经祖细胞中 FUBP1 缺失时，LSD1+8a 下调，从而损害终末神经元分化和成熟。在 FUBP1 下调的神经祖细胞中增强 LSD1+8a 表达可恢复终末分化并抑制肿瘤发生；因此，LSD1+8a 是 FUBP1 依赖性神经元分化的必然效应器。这些发现确立了 FUBP1 在神经元分化中的直接作用，并解释了其在神经系统中的肿瘤抑制功能。 FUBP1 是神经元终末分化所必需的肿瘤抑制因子。FUBP1 促进神经元特异性 LSD1 外显子 8a 的包含。FUBP1 和 IDH1 突变会导致神经祖细胞分化受损。在这篇文章中，Paik 及其同事证明 FUBP1 在促进神经元终末分化中发挥着不可或缺的作用，而 FUBP1 的缺乏会干扰早期出生的神经元细胞退出细胞周期，并使这些细胞易于转化。这些发现解释了 FUBP1 如何在中枢神经系统中发挥独特的肿瘤抑制作用。
Loss of a cell's ability to terminally differentiate because of mutations is a selected genetic event in tumorigenesis. Genomic analyses of low-grade glioma have reported recurrent mutations of far upstream element-binding protein 1 (FUBP1). Here, we show that FUBP1 expression is dynamically regulated during neurogenesis and that its downregulation in neural progenitors impairs terminal differentiation and promotes tumorigenesis collaboratively with expression of IDH1R132H. Mechanistically, collaborative action between SRRM4 and FUBP1 is necessary for mini-exon splicing of the neurospecific LSD1+8a isoform. LSD1+8a was downregulated upon loss of FUBP1 in neural progenitors, thereby impairing terminal neuronal differentiation and maturation. Reinforcing LSD1+8a expression in FUBP1-downregulated neural progenitors restored terminal differentiation and suppressed tumorigenesis; hence, LSD1+8a is an obligatory effector of FUBP1-dependent neuronal differentiation. These findings establish a direct role for FUBP1 in neuronal differentiation and also explain its tumor-suppressor function in the nervous system. FUBP1 is the tumor suppressor necessary for terminal differentiation of neurons FUBP1 promotes inclusion of neuron-specific LSD1 exon 8a FUBP1 and IDH1 mutations converge on impaired differentiation of neural progenitors In this article, Paik and colleagues demonstrate that FUBP1 plays an indispensable role in promoting terminal differentiation of neurons and that lack of FUBP1 interferes with early-born neuronal cells exiting the cell cycle and predisposes these cells for transformation. These findings explain how FUBP1 serves uniquely as a tumor suppressor in the CNS.
登录
查看更多内容
影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
DOI：
10.1073/pnas.1310607110
发表时间：
2013-07-16
影响因子：
11.1
作者：
Li, Huang;Wang, Zhijia;Feng, Ying
通讯作者：
Feng, Ying
影响因子：
13.9
作者：
Kriegstein A;Alvarez-Buylla A
通讯作者：
Alvarez-Buylla A
影响因子：
4.8
作者：
Jacob, Aishwarya G.;Singh, Ravi K.;Chandler, Dawn S.
通讯作者：
Chandler, Dawn S.
DOI：
10.1126/science.1164382
发表时间：
2008-09-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Parsons DW;Jones S;Zhang X;Lin JC;Leary RJ;Angenendt P;Mankoo P;Carter H;Siu IM;Gallia GL;Olivi A;McLendon R;Rasheed BA;Keir S;Nikolskaya T;Nikolsky Y;Busam DA;Tekleab H;Diaz LA Jr;Hartigan J;Smith DR;Strausberg RL;Marie SK;Shinjo SM;Yan H;Riggins GJ;Bigner DD;Karchin R;Papadopoulos N;Parmigiani G;Vogelstein B;Velculescu VE;Kinzler KW
通讯作者：
Kinzler KW