NSrp70 is a lymphocyte-essential splicing factor that controls thymocyte development

Abstract

Alternative pre-mRNA splicing is a critical step to generate multiple transcripts, thereby dramatically enlarging the proteomic diversity. Thus, a common feature of most alternative splicing factor knockout models is lethality. However, little is known about lineage-specific alternative splicing regulators in a physiological setting. Here, we report that NSrp70 is selectively expressed in developing thymocytes, highest at the double-positive (DP) stage. Global splicing and transcriptional profiling revealed that NSrp70 regulates the cell cycle and survival of thymocytes by controlling the alternative processing of various RNA splicing factors, including the oncogenic splicing factor SRSF1. A conditional-knockout of Nsrp1 (NSrp70-cKO) using CD4Cre developed severe defects in T cell maturation to single-positive thymocytes, due to insufficient T cell receptor (TCR) signaling and uncontrolled cell growth and death. Mice displayed severe peripheral lymphopenia and could not optimally control tumor growth. This study establishes a model to address the function of lymphoid-lineage-specific alternative splicing factor NSrp70 in a thymic T cell developmental pathway.

BCL6 is required for the thymic development of TCRαβ + CD8αα + intraepithelial lymphocyte lineage

“…( A ) The statistic data of percentages and cell numbers of thymic IELps, PD1 + IELps, and intestinal CD8αα + αβ IELs from Bcl6 fl/fl VavP Bcl2 and Bcl6 fl/fl Cd4 cre VavP Bcl2 mice. ( B ) Venn plot shows overlapped DEGs in WT agonist-p ( n = 2) compared with DP thymocytes ( n = 3) and BCL6-regulated DEGs in WT agonist-p compared with BCL6-deficient agonist-p [DP RNA-seq data were obtained and reanalyzed from GEO: GSE168379 ( 49 )]. ( C ) GSEA analysis of top 200 DP and IELp signature genes (FDR < 0.01, FPKM > 10) enriched in the transcriptome of WT and BCL6-deficient agonist-p. ( D ) Heatmap for representative DP- and IELp-related genes from RNA-seq data of WT and BCL6-deficient agonist-p. ( E ) Venn plot showed overlapped genes that were bound by BCL6 in T H 9 cells and BCL6-regulated DEGs in WT agonist-p compared with BCL6-deficient ones.…”

“…To examine how BCL6 regulates the differentiation of IELps from DP precursors, we first reanalyzed the published RNA-seq data of WT DP thymocytes ( 49 ) together with our RNA-seq data on WT agonist-selected precursors. As a result of strong TCR signal reception in agonist-selected precursors, we identified a total of 2695 up-regulated and 1275 down-regulated protein-coding genes (fig.…”

Increased Expression of SRSF1 Predicts Poor Prognosis in Multiple Myeloma

“…To protect T cell intrathymic maturation, SRSF1 regulates various cellular processes, such as cell differentiation, proliferation, apoptosis, and type I interferon signaling pathway [ 21 ]. NSrp70, a splicing factor, regulates thymocyte development via partial alternative processing of SRSF1 [ 22 ]. Sinnakannu et al reported that high SRSF1 expression in chronic myeloid leukemia was associated with imatinib resistance, which was mediated by the SRSF1/PRKCH/PLCH1 axis [ 24 ].…”

“…Additionally, studies about the role of SRSF1 in normal hemopoiesis and hematological malignancies have been emerging as well. For example, SRSF1 is a critical post-transcriptional regulator in the late stage of thymocyte development [ 21 , 22 ]. Upregulated SRSF1, with the cooperation of PRTM1, acts as an adverse factor in pediatric acute lymphoblastic leukemia [ 23 ].…”

Transcriptional Regulation of Early T-Lymphocyte Development in Thymus

“…Interestingly, nuclear speckle-related protein 70 (NSrp70) is selectively expressed on developing thymocytes and highest at DP stage. NSrp70 could regulate cell cycle and survival of thymocytes by governing the alternative processing of various RNA splicing factors, such as oncogenic serine/arginine-rich splicing factor SRSF1 ( 63 ). This finding may provide a new angle to dig up larger scale of transcription network in DP survival.…”