We characterized the regulatory mechanisms and role in human myeloid cell survival and differentiation of PRPF40A, a splicing factor lacking a canonical RNA Binding Domain. Upon PRPF40A knockdown, HL-60 cells displayed increased cell death, decreased proliferation and slight differentiation phenotype with upregulation of immune activation genes. Suggestive of both redundant and specific functions, cell death but not proliferation was rescued by overexpression of its paralog PRPF40B. Transcriptomic analysis revealed the predominant role of PRPF40A as an activator of cassette exon inclusion of functionally relevant splicing events. Mechanistically, the exons exclusively upregulated by PRPF40A are flanked by short and GC-rich introns which tend to localize to nuclear speckles in the nucleus center. These PRPF40A regulatory features are shared with other splicing regulators such as SRRM2, SON, PCBP1/2, and to a lesser extent TRA2B and SRSF2, as a part of a functional network that regulates splicing partly via co-localization in the nucleus.

中文翻译：

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PRPF40A 诱导外显子包含在富含 GC 的区域，这对人类骨髓细胞分化很重要


我们描述了 PRPF40A（一种缺乏典型 RNA 结合域的剪接因子）在人骨髓细胞存活和分化中的调节机制和作用。 PRPF40A 敲低后，HL-60 细胞表现出细胞死亡增加、增殖减少和轻微分化表型，同时免疫激活基因上调。其旁系同源物 PRPF40B 的过表达挽救了细胞死亡而非增殖，这表明存在冗余和特定功能。转录组分析揭示了 PRPF40A 作为功能相关剪接事件的盒式外显子包含激活剂的主要作用。从机制上讲，PRPF40A 专门上调的外显子两侧是短且富含 GC 的内含子，这些内含子往往定位于细胞核中心的核斑点。这些 PRPF40A 调节功能与其他剪接调节器（如 SRRM2、SON、PCBP1/2）以及较小程度上的 TRA2B 和 SRSF2 共享，作为功能网络的一部分，部分通过细胞核中的共定位来调节剪接。