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.

胚胎干细胞（ESC）发育成神经元需要复杂的转录、剪接和翻译调节，但这些过程如何相互关联尚不清楚。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，从而在发育早期产生 DPF2-S 亚型。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。这些替代的 DPF2 亚型诱导了不同的细胞表型和基因表达程序。我们鉴定了每种 DPF2 同种型富集的染色质结合位点，以及两者结合的位点。在ESC中，DPF2-S优先位点与多能因子结合。在神经元祖细胞中，DPF2-S 位点与核因子 I (NFI) 结合，而 DPF2-L 位点与 CCCTC 结合因子 (CTCF) 结合。 DPF2-S 位点表现出增强子修饰，而 DPF2-L 位点表现出启动子修饰。因此，选择性剪接会重定向 BAF 复合物的靶向，从而影响神经元发育过程中的染色质组织。