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Abstract：
Development of embryonic stem cells (ESCs) into neurons requires intricate regulation of transcription, splicing, and translation, but how these processes interconnect is not understood. We found that polypyrimidine tract binding protein 1 (PTBP1) controls splicing of DPF2, a subunit of BRG1/BRM-associated factor (BAF) chromatin remodeling complexes. Dpf2 exon 7 splicing is inhibited by PTBP1 to produce the DPF2-S isoform early in development. During neuronal differentiation, loss of PTBP1 allows exon 7 inclusion and DPF2-L expression. Different cellular phenotypes and gene expression programs were induced by these alternative DPF2 isoforms. We identified chromatin binding sites enriched for each DPF2 isoform, as well as sites bound by both. In ESC, DPF2-S preferential sites were bound by pluripotency factors. In neuronal progenitors, DPF2-S sites were bound by nuclear factor I (NFI), while DPF2-L sites were bound by CCCTC-binding factor (CTCF). DPF2-S sites exhibited enhancer modifications, while DPF2-L sites showed promoter modifications. Thus, alternative splicing redirects BAF complex targeting to impact chromatin organization during neuronal development.
摘要：
胚胎干细胞（ESCs）发育为神经元需要复杂的转录调控，拼接,翻译,但是这些过程如何互连还不清楚。我们发现多嘧啶束结合蛋白1（PTBP1）控制DPF2的剪接，DPF2是BRG1/BRM相关因子（BAF）染色质重塑复合物的亚基。Dpf2外显子7剪接被PTBP1抑制以在发育早期产生DPF2-S同工型。在神经元分化过程中,PTBP1的缺失允许外显子7包含和DPF2-L表达。通过这些替代的DPF2同种型诱导不同的细胞表型和基因表达程序。我们确定了每个DPF2亚型富集的染色质结合位点，以及两者绑定的网站。在ESC,DPF2-S优先位点被多能性因子结合。在神经元祖细胞中，DPF2-S位点与核因子I（NFI）结合，而DPF2-L位点被CCCTC结合因子(CTCF)结合。DPF2-S位点表现出增强子修饰，而DPF2-L位点显示启动子修饰。因此，选择性剪接重定向BAF复合物靶向以影响神经元发育过程中的染色质组织。
