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SRSF1 Deficiency Impairs the Late Thymocyte Maturation and the CD8 Single-Positive Lineage Fate Decision.

ABSTRACT: The underlying mechanisms of thymocyte development and lineage determination remain incompletely understood, and the emerging evidences demonstrated that RNA binding proteins (RBPs) are deeply involved in governing T cell fate in thymus. Serine/arginine-rich splicing factor 1 (SRSF1), as a classical splicing factor, is a pivotal RBP for gene expression in various biological processes. Our recent study demonstrated that SRSF1 plays essential roles in the development of late thymocytes by modulating the T cell regulatory gene networks post-transcriptionally, which are critical in response to type I interferon signaling for supporting thymocyte maturation. Here, we report SRSF1 also contributes to the determination of the CD8⁺ T cell fate. By specific ablation of SRSF1 in CD4⁺CD8⁺ double positive (DP) thymocytes, we found that SRSF1 deficiency impaired the maturation of late thymocytes and diminished the output of both CD4⁺ and CD8⁺ single positive T cells. Interestingly, the ratio of mature CD4⁺ to CD8⁺ cells was notably altered and more severe defects were exhibited in CD8⁺ lineage than those in CD4⁺ lineage, reflecting the specific function of SRSF1 in CD8⁺ T cell fate decision. Mechanistically, SRSF1-deficient cells downregulate their expression of Runx3, which is a crucial transcriptional regulator in sustaining CD8⁺ single positive (SP) thymocyte development and lineage choice. Moreover, forced expression of Runx3 partially rectified the defects in SRSF1-deficient CD8⁺ thymocyte maturation. Thus, our data uncovered the previous unknown role of SRSF1 in establishment of CD8⁺ cell identity.

SUBMITTER: Ji C

PROVIDER: S-EPMC8825371 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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SRSF1 Deficiency Impairs the Late Thymocyte Maturation and the CD8 Single-Positive Lineage Fate Decision.

Ji Ce C Bao Li L Yuan Shunzong S Qi Zhihong Z Wang Fang F You Menghao M Yu Guotao G Liu Jingjing J Cui Xiao X Wang Zhao Z Liu Juanjuan J Guo Wenhui W Feng Mingxia M Chen Feng F Kang Youmin Y Yu Shuyang S

Frontiers in immunology 20220126

The underlying mechanisms of thymocyte development and lineage determination remain incompletely understood, and the emerging evidences demonstrated that RNA binding proteins (RBPs) are deeply involved in governing T cell fate in thymus. Serine/arginine-rich splicing factor 1 (SRSF1), as a classical splicing factor, is a pivotal RBP for gene expression in various biological processes. Our recent study demonstrated that SRSF1 plays essential roles in the development of late thymocytes by modulati ...[more]

PMID: 35154164

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Project description:First-hits in the multi-hit process of leukemogenesis originate in germline or hematopoietic stem cells (HSCs), yet leukemia-initiating cells (LICs) usually have a lineage-committed phenotype. The molecular mechanisms underlying this compartment shift during leukemia evolution have not been a major focus of investigation and remain poorly understood. Here a mechanism underlying this shift was examined in the context of Runx1 deficiency, a frequent leukemia-initiating event. Lineage-negative cells isolated from the bone marrow of Runx1-haploinsufficient and wild-type control mice were cultured in granulocyte-colony-stimulating factor to force lineage commitment. Runx1-haploinsufficient cells demonstrated significantly greater and persistent exponential cell growth than wild-type controls. Not surprisingly, the Runx1-haploinsufficient cells were differentiation-impaired, by morphology and by flow-cytometric evaluation for granulocyte differentiation markers. Interestingly, however, this impaired differentiation was not because of decreased granulocyte lineage commitment, as RNA and protein upregulation of the master granulocyte lineage-commitment transcription factor Cebpa, and Hoxb4 repression, was similar in wild-type and Runx1-haploinsufficient cells. Instead, RNA and protein expression of Cebpe, a key driver of progressive maturation after lineage commitment, were significantly decreased in Runx1-haploinsufficient cells. Primary acute myeloid leukemia cells with normal cytogenetics and RUNX1 mutation also demonstrated this phenotype of very high CEBPA mRNA expression but paradoxically low expression of CEBPE, a CEBPA target gene. Chromatin-immunoprecipitation analyses suggested a molecular mechanism for this phenotype: in wild-type cells, Runx1 binding was substantially greater at the Cebpe than at the Cebpa enhancer. Furthermore, Runx1 deficiency substantially diminished high-level Runx1 binding at the Cebpe enhancer, but lower-level binding at the Cebpa enhancer was relatively preserved. Thus, Runx1-deficiency permits Cebpa upregulation and the exponential cell growth that accompanies lineage commitment, but by impairing activation of Cebpe, a key proliferation-terminating maturation gene, extends this exponential growth. These mechanisms facilitate germline cell or HSC of origin, yet evolution into LIC with lineage-committed phenotype.

Dataset Information

SRSF1 Deficiency Impairs the Late Thymocyte Maturation and the CD8 Single-Positive Lineage Fate Decision.

Publications

SRSF1 Deficiency Impairs the Late Thymocyte Maturation and the CD8 Single-Positive Lineage Fate Decision.

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