SRSF1调控人胚胎干细胞向造血分化

SRSF1 Regulates Hematopoietic Differentiation of Human Embryonic Stem Cells

可变剪接属于转录后调控,通过调控细胞增殖、分化等生物学过程影响细胞的命运决定与谱系分化。现有研究表明,剪接相关因子在造血发育过程中发挥重要作用,但剪接因子SRSF1在早期造血分化过程中是否有功能仍然未有报道。早期的研究证实,剪接因子SRSF2可通过调控NUMB的可变剪接影响生血内皮细胞产生。在人胚胎干细胞造血分化模型不同阶段细胞的RNA-seq以及RT-qPCR数据均表明,SRSF2与SRSF1在造血分化过程中的表达模式相似,在生血内皮产生阶段表达变化最显著。为了探究SRSF1在造血分化过程中是否影响生血内皮细胞的产生,该研究构建了诱导性过表达SRSF1的人胚胎干细胞稳定株,发现过表达SRSF1促进生血内皮细胞的产生;并且通过RNA干扰技术在生血内皮细胞产生阶段敲低剪接因子SRSF1,发现敲低SRSF1能抑制生血内皮细胞的产生。通过可变剪接体外报告系统证实剪接因子SRSF1能够结合到NUMB exon 9上的相关位点并且促进NUMB短转录本的产生。该研究证实,SRSF1能够影响生血内皮阶段,这可能是通过调控NUMB的可变剪接完成的,为生血内皮的产生提供了另一项理论依据。

Alternative splicing is a post-transcriptional process which impacts cell fate decision and lineage differentiation via regulating cell proliferation and differentiation.The prior study revealed splicing factor SRSF2 modulated the generation of HE (hemogenic endothelial cells) mainly through alternative splicing of NUMB transcripts during inducing hematopoietic differentiation from hESCs (human embryonic stem cells).Despite SRSF1 shared the similar expression pattern as SRSF2,its role in early hematopoietic differentiation is still largely unknown.In order to explore whether SRSF1 affects the production of HE during hematopoietic differentiation,this study constructed an inducible stable cell line of hESCs with overexpressed SRSF1 and found that overexpression of SRSF1 promoted the production of HE.In addition,knockdown of SRSF1 during the generation of HE by RNA interference technology can inhibit the production of HE.SRSF1 can bind to NUMB exon 9 and promote the production of NUMB short isoform,which were confirmed by the vitro alternative splicing reporter system.This study confirmed that SRSF1 could affect the production of hemogenic endothelial cells,possibly by regulating the alternative splicing of NUMB.