The spliceosome component Usp39 controls B cell development by regulating immunoglobulin gene rearrangement

The spliceosome is a large ribonucleoprotein complex responsible for pre-mRNA splicing and genome stability maintenance. Disruption of the spliceosome activity may lead to developmental disorders and tumorigenesis. However, the physiological role that the spliceosome plays in B cell development and function is still poorly defined. Here, we demonstrate that ubiquitin-specific peptidase 39 (Usp39), a spliceosome component of the U4/U6.U5 tri-snRNP complex, is essential for B cell development. Ablation of Usp39 in B cell lineage blocks pre-pro-B to pro-B cell transition in the bone marrow, leading to a profound reduction of mature B cells in the periphery. We show that Usp39 specifically regulates immunoglobulin gene rearrangement in a spliceosome-dependent manner, which involves modulating chromatin interactions at the Igh locus. Moreover, our results indicate that Usp39-deletion reduces the pre-malignant B cells in EÎŒ-Myc transgenic mice and significantly improves their survival. RNA-Seq of pre-pro-B cells in Usp39 fl/fl and Usp39 fl/fl mb1-cre mice; RNA-Seq of small pre-B cells in Usp39 fl/fl and Usp39 fl/fl cd19-cre mice; Hi-C-Seq of pre-pro-B cells in Usp39 fl/fl and Usp39 fl/fl mb1-cre mice剪接体（spliceosome）是一类大型核糖核蛋白复合物，负责前体mRNA剪接与基因组稳定性维持。剪接体活性异常可引发发育障碍与肿瘤发生。然而，剪接体在B细胞发育及功能中的生理作用仍未明确。本研究证实，泛素特异性肽酶39（ubiquitin-specific peptidase 39，Usp39）作为U4/U6.U5三小核核糖核蛋白复合物（U4/U6.U5 tri-snRNP complex）的剪接体组分，对B细胞发育至关重要。B细胞谱系中Usp39的敲除会阻断骨髓内前前B细胞向前B细胞的转化，进而导致外周成熟B细胞大幅减少。研究发现，Usp39以剪接体依赖的方式特异性调控免疫球蛋白基因重排，该过程涉及对免疫球蛋白重链基因座（Igh locus）处染色质相互作用的调控。此外，实验结果表明，Usp39敲除可减少Eμ-Myc转基因小鼠体内的癌前B细胞，并显著延长小鼠生存期。本研究涉及的测序数据集包括：Usp39 fl/fl与Usp39 fl/fl mb1-cre小鼠前前B细胞的RNA测序（RNA-Seq）；Usp39 fl/fl与Usp39 fl/fl cd19-cre小鼠小前B细胞的RNA测序（RNA-Seq）；Usp39 fl/fl与Usp39 fl/fl mb1-cre小鼠前前B细胞的Hi-C测序（Hi-C-Seq）