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The change of mRNA stability upon T cell activation

ABSTRACT: T cell activation is a well-established model for studying cellular responses to exogenous stimulation. In this study, we performed BruChase-Seq to experimentally monitor the expression dynamics of nascent transcripts in resting and activated CD4+ T cells, and applied computational modeling to investigate the impact of IR on the kinetics of mRNA degradation. As expected, intron retained transcripts are considerably less stable than spliced transcripts. In addition, the decrease in the steady-state IR level in activated CD4+ T cells are in part due to increased splicing efficiency and further stabilization of spliced transcripts. We propose that coordination between splicing regulation and mRNA stability may provide a novel paradigm to achieve spatiotemporal control of gene expression during T cell activation. We also found the mRNA stability change is not due to the 3’UTR-isoform choice but may be regulated by the RBP for example the LARP4 is the most significant binding protein in 3’ UTR of the β1-decreased genes. Furthermore, the mRNAs of the activated CD4+ T cells in LARP4 Knock-out (KO) mice showed the decreased stability and comparable transcriptional level for some genes including the NFkB1 and PSMD7 when comparing to the wild-type (WT) mice, resulting in the down-regulation of these genes. Finally, the LARP4 KO down-regulated NFkB1 target genes such as IL2 and IFNG upon CD4+ T cell activation, which is critical for the T cell proliferation and function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE113730 | GEO | 2020/07/21

REPOSITORIES: GEO

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Project description:T cell activation leads to dramatic changes in cellular phenotype. We used CD3/CD28-activated human CD4 T cells to study how RNA binding proteins define the post-transcriptional landscape. Using RIPseq, we identified the RNA interactome of U2AF2 and show at the global level that U2AF2 binds the majority of transcripts that are differentially expressed and/or alternatively spliced during CD4 T cell activation. A unique protein interactome centered on U2AF2 is assembled in response to activation. Knocking down specific U2AF2 interacting partners (U2AF1, SYNCRIP, SRRM2, ILF2) selectively affects cytokine secretion and expression of activation markers. Furthermore, the expression and/or alternative splicing of transcripts important for immune cell function are also affected by knocking down these U2AF2 interacting proteins. U2AF1 and SYNCRIP knockdowns affect the proteins and transcripts bound to U2AF2, altering the transcriptome. Our work highlights the importance of RNA binding protein complexes in regulating the differential expression and alternative splicing that defines T cell activation. HTA 2.0 microarray results of total from a primary CD4 T cell culture after treatment with siRNAs (Control, U2AF1, SRRM2, SYNCRIP, and ILF2) and 24 hours after anti-CD3/CD28 bead activation Please note that the Series supplementary 'TotalRNA_HTA2_all_siRNA_100414.xslx' file has multiple worksheets containing: 1) Differentially expressed genes in ctrl siRNA vs. U2AF1 siRNA; 2) Differntially spliced genes in ctrl siRNA vs. U2AF1 siRNA; 3) Differentially spliced exons in ctrl siRNA vs. U2AF1 siRNA; 4) Differentially expressed genes in ctrl siRNA vs. SRRM2 siRNA; 5) Differntially spliced genes in ctrl siRNA vs. SRRM2 siRNA; 6) Differentially spliced exons in ctrl siRNA vs. SRRM2 siRNA; 7) Differentially expressed genes in ctrl siRNA vs. SYNCRIP siRNA; 8) Differntially spliced genes in ctrl siRNA vs. SYNCRIP siRNA; 9) Differentially spliced exons in ctrl siRNA vs. SYNCRIP siRNA; 10) Differentially expressed genes in ctrl siRNA vs. ILF2 siRNA; 11) Differntially spliced genes in ctrl siRNA vs. ILF2 siRNA; 12) Differentially spliced exons in ctrl siRNA vs. ILF2 siRNA

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The change of mRNA stability upon T cell activation

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