Systematic exploration of dynamic splicing networks reveals conserved multistage regulators of neurogenesis.
Systematic exploration of dynamic splicing networks reveals conserved multistage regulators of neurogenesis.
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DOI：
10.1016/j.molcel.2022.06.036
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发表时间：
2022-08-18
期刊：
影响因子：
16
通讯作者：
Blencowe, Benjamin J.
中科院分区：
文献类型：
--
作者：
Han, Hong;Best, Andrew J.;Braunschweig, Ulrich;Mikolajewicz, Nicholas;Li, Jack Daiyang;Roth, Jonathan;Chowdhury, Fuad;Mantica, Federica;Nabeel-Shah, Syed;Parada, Guillermo;Brown, Kevin R.;O'Hanlon, Dave;Wei, Jiarun;Yao, Yuxi;Abou Zid, Abdelrahman;Comsa, Lim Caden;Jen, Mark;Wang, Jenny;Datti, Alessandro;Gonatopoulos-Pournatzis, Thomas;Weatheritt, Robert J.;Greenblatt, Jack F.;Wrana, Jeffrey L.;Irimia, Manuel;Gingras, Anne-Claude;Moffat, Jason;Blencowe, Benjamin J.
选择性剪接(AS)是一个重要的调节层；然而，在发育转变过程中控制功能协调剪接程序的因素却知之甚少。在这里，我们使用筛选策略来确定控制动态剪接事件的因素，这些因素对哺乳动物神经发生至关重要。在以前未知的调节子中，Rbm38广泛地发挥负向控制神经AS的作用，部分是通过已建立的剪接抑制因子PTBP1介导的相互作用。令人惊讶的是，人们发现Puf60是一种普遍存在的因子，可以促进神经拼接模式。这一活动需要一个保守的、神经分化的外显子来重塑Puf60辅助因子相互作用。在胚胎干细胞和小鼠神经发生的不同阶段，去除这个外显子会重新连接成不同的网络。单细胞转录组分析进一步揭示了Rbm38和Puf60亚型在建立神经元身份中的不同作用。我们的结果描述了以前未知的神经发生调控因子的重要作用，并建立了广泛表达的剪接因子中的替代外显子如何协调对细胞分化的时间控制。Han，Best，Braunschweig等人。使用Neu-Spar-Seq屏幕来发现调节与神经发生相关的时空剪接网络的因素。将筛选数据与分子特征和单细胞转录学相结合，揭示了Rbm38和Puf60亚型在调控剪接模式和建立神经元身份中的多阶段作用。
Alternative splicing (AS) is a critical regulatory layer; yet, factors controlling functionally coordinated splicing programs during developmental transitions are poorly understood. Here, we employ a screening strategy to identify factors controlling dynamic splicing events important for mammalian neurogenesis. Among previously unknown regulators, Rbm38 acts widely to negatively control neural AS, in part through interactions mediated by the established repressor of splicing, Ptbp1. Puf60, a ubiquitous factor, is surprisingly found to promote neural splicing patterns. This activity requires a conserved, neural-differential exon that remodels Puf60 co-factor interactions. Ablation of this exon rewires distinct AS networks in embryonic stem cells and at different stages of mouse neurogenesis. Single-cell transcriptome analyses further reveal distinct roles for Rbm38 and Puf60 isoforms in establishing neuronal identity. Our results describe important roles for previously unknown regulators of neurogenesis and establish how an alternative exon in a widely expressed splicing factor orchestrates temporal control over cell differentiation. Han, Best, Braunschweig et al. employ a Neu-SPAR-seq screen to discover factors that regulate spatiotemporal splicing networks associated with neurogenesis. Integration of the screen data with molecular characterization and single-cell transcriptomics reveals multistage roles for Rbm38 and Puf60 isoforms in the regulation of splicing patterns and establishment of neuronal identity.
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影响因子：
11.4
作者：
Crichlow, Gregg V.;Zhou, Hongwen;Hsiao, Hsin-hao;Frederick, Kendra B.;Debrosse, Maxime;Yang, Yuande;Folta-Stogniew, Ewa J.;Chung, Hye-Jung;Fan, Chengpeng;De La Cruz, Enrique M.;Levens, David;Lolis, Elias;Braddock, Demetrios
通讯作者：
Braddock, Demetrios
影响因子：
3.4
作者：
Deutsch, Eric W.;Mendoza, Luis;Shteynberg, David;Farrah, Terry;Lam, Henry;Tasman, Natalie;Sun, Zhi;Nilsson, Erik;Pratt, Brian;Prazen, Bryan;Eng, Jimmy K.;Martin, Daniel B.;Nesvizhskii, Alexey I.;Aebersold, Ruedi
通讯作者：
Aebersold, Ruedi
影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
DOI：
10.1038/nrm.2017.27
发表时间：
2017-07
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Baralle FE;Giudice J
通讯作者：
Giudice J
影响因子：
7
作者：
Braunschweig U;Barbosa-Morais NL;Pan Q;Nachman EN;Alipanahi B;Gonatopoulos-Pournatzis T;Frey B;Irimia M;Blencowe BJ
通讯作者：
Blencowe BJ