Splicing factor SF3B1K700E mutant dysregulates erythroid differentiation via aberrant alternative splicing of transcription factor TAL1.
Splicing factor SF3B1K700E mutant dysregulates erythroid differentiation via aberrant alternative splicing of transcription factor TAL1.
复制标题
剪接因子 SF3B1(K700E) 突变体通过转录因子 TAL1 的异常选择性剪接调节红细胞分化
DOI：
10.1371/journal.pone.0175523
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Zhao X
中科院分区：
文献类型：
--
作者：
Jin S;Su H;Tran NT;Song J;Lu SS;Li Y;Huang S;Abdel-Wahab O;Liu Y;Zhao X
超过60%的髓系发育不良综合征(MDS)包含SF3B1、U2AF、SRSF2和ZRSR2等剪接因子编码基因的突变。SF3B1基因突变与80%的环状铁粒母细胞(RARS)难治性贫血有关，RARS是MDS的一种亚型。在SF3B1的突变中，SF3B1K700E是最常见的突变位点。然而，剪接因子突变如何导致红细胞生成缺陷的分子机制尚不清楚。在免疫共沉淀实验中，SF3B1K700E突变体与一种RNA结合蛋白RBM15结合，该蛋白比野生型SF3B1蛋白更强。此外，K700E突变还改变了转录因子TAL1和GATA1的RNA剪接。通过选择性RNA剪接，产生了一个新的短TAL1转录变异体(TAL1s)。SF3B1和RBM15之间的相互作用增强，促进全长TAL1(TAL1fl)mRNA的产生，而通过PRMT1介导的降解途径降低RBM15的蛋白水平，改变TAL1s/TAL1fl的比率，有利于TAL1s。TAL1s含有螺旋-环-螺旋DNA结合域，但不包含DNA结合域上游的N末端区域。TAL1S蛋白失去了与ETO2的相互作用，ETO2抑制了早期的红细胞生成。在这条静脉中，TAL1s的过表达刺激了人白血病K562细胞中β-Hb的转录，并促进了在含促红细胞生成素的培养液中培养的人脐血CD34+细胞的红系分化。因此，SF3B1的突变可能通过调节转录因子TAL1的选择性RNA剪接来阻止红细胞生成，靶向PRMT1可能缓解MDS患者的贫血症状。
More than 60% of myeloid dysplasia syndrome (MDS) contains mutations in genes encoding for splicing factors such as SF3B1, U2AF, SRSF2 and ZRSR2. Mutations in SF3B1 are associated with 80% cases of refractory anemia with ring sideroblast (RARS), a subtype of MDS. SF3B1K700E is the most frequently mutated site among mutations on SF3B1. Yet the molecular mechanisms on how mutations of splicing factors lead to defective erythropoiesis are not clear. SF3B1K700E mutant binds to an RNA binding protein, RBM15, stronger than the wild type SF3B1 protein in co-immunoprecipitation assays. In addition, K700E mutant alters the RNA splicing of transcription factors TAL1 and GATA1. Via alternative RNA splicing, a novel short TAL1 transcript variant (TAL1s) is generated. Enhanced interaction between SF3B1 and RBM15 promotes the production of full-length TAL1 (TAL1fl) mRNA, while reduction of RBM15 protein level via PRMT1-mediated degradation pathway changes TAL1s/TAL1fl ratio in favor of TAL1s. TAL1s contains the helix-loop-helix DNA binding domain but not the N terminal region upstream of the DNA binding domain. The TAL1s protein loses its interaction with ETO2, which represses early erythropoiesis. In this vein, overexpression of TAL1s stimulates the transcription of β-hemoglobin in human leukemia K562 cells and promotes erythroid differentiation of human cord blood CD34+ cells cultured in erythropoietin-containing medium. Therefore, mutations of SF3B1 may block erythropoiesis via dysregulation of alternative RNA splicing of transcription factor TAL1, and targeting PRMT1 may alleviate the anemic symptoms in MDS patients.