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The RNA-binding protein Arpp21 interacts with and promotes Rag1 target mRNA expression to enable TCR rearrangement [RNA-seq]

ABSTRACT: Post-transcriptional control by RNA-binding proteins (RBPs) is an essential layer of gene regulation in lymphocytes. Here, we show how members of the R3hdm RBP family regulate gene expression and promote the development of thymocytes. R3hdm paralogs with an intact R3H/SUZ domain bound mRNAs of other RBPs including Roquin-1, Roquin-2 and Nufip2, and augmented their expression. Arpp21 (R3hdm3) expression was restricted to thymocyte stages when Rag proteins recombine gene segments of the TCR variable region. Crosslinking and immunoprecipitation of Arpp21 in thymocytes revealed prominent binding to the Rag1 mRNA, and Arpp21 increased Rag1 3'-UTR reporter expression. Consequently, Arpp21–deficient mice showed decreased Rag1 expression in thymocytes, delayed TCR rearrangement, reduced frequencies of cells with TCR expression and a partial block of thymocyte development. The Arpp21 protein was regulated by Ca2+–signals that induced phosphorylation, polyubiquitination and proteasomal degradation. These findings involve general redundant functions of R3hdm RBP family proteins and show how stage-specific upregulation of Arpp21 in thymocytes promotes Rag1 expression preceding recombination while productive TCR rearrangement ceases this function.

ORGANISM(S): Mus musculus

PROVIDER: GSE198797 | GEO | 2024/01/16

REPOSITORIES: GEO

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The RNA-binding protein Arpp21 interacts with and promotes Rag1 target mRNA expression to enable TCR rearrangement [CLIP-seq]

Project description:Post-transcriptional control by RNA-binding proteins (RBPs) is an essential layer of gene regulation in lymphocytes. Here, we show how members of the R3hdm RBP family regulate gene expression and promote the development of thymocytes. R3hdm paralogs with an intact R3H/SUZ domain bound mRNAs of other RBPs including Roquin-1, Roquin-2 and Nufip2, and augmented their expression. Arpp21 (R3hdm3) expression was restricted to thymocyte stages when Rag proteins recombine gene segments of the TCR variable region. Crosslinking and immunoprecipitation of Arpp21 in thymocytes revealed prominent binding to the Rag1 mRNA, and Arpp21 increased Rag1 3'-UTR reporter expression. Consequently, Arpp21–deficient mice showed decreased Rag1 expression in thymocytes, delayed TCR rearrangement, reduced frequencies of cells with TCR expression and a partial block of thymocyte development. The Arpp21 protein was regulated by Ca2+–signals that induced phosphorylation, polyubiquitination and proteasomal degradation. These findings involve general redundant functions of R3hdm RBP family proteins and show how stage-specific upregulation of Arpp21 in thymocytes promotes Rag1 expression preceding recombination while productive TCR rearrangement ceases this function.

2024-01-16 | GSE198796 | GEO

The thymocyte-specific RNA-binding protein Arpp21 provides TCR repertoire diversity by binding to the 3'-UTR and promoting Rag1 mRNA expression

Project description:The regulation of thymocyte development by RNA-binding proteins (RBPs) is largely unexplored. We identified 642 RBPs in the thymus and focused on Arpp21, which shows selective and dynamic expression in early thymocytes. Arpp21 was downregulated in response to T cell receptor (TCR) and Ca2+ signals. Downregulation required Stim1/Stim2 and CaMK4 expression and involved Arpp21 protein phosphorylation, polyubiquitination and proteasomal degradation. Arpp21 directly bound RNA through its R3H domain, with a preference for uridine-rich motifs, promoting the expression of target mRNAs. Analysis of the Arpp21-bound transcriptome revealed strong interactions with the Rag1 3'-UTR. Arpp21-deficient thymocytes showed reduced Rag1 expression, delayed TCR rearrangement and a less diverse TCR repertoire. This phenotype was recapitulated in Rag1 3'-UTR mutant mice harboring a deletion of the Arpp21 response region. These findings show how thymocyte-specific Arpp21 promotes Rag1 expression to enable TCR repertoire diversity until signals from the TCR terminate Arpp21 and Rag1 activities.

2023-03-31 | MSV000091606 | MassIVE

Ezh2 deficiency in double negative thymocytes

Project description:Expression profiles from Rag1 mutant and Rag1/Ezh2 double mutant double negative thymocytes Keywords = Rag1 Keywords = Ezh2 Keywords = Thymocyte Keywords: repeat sample

2005-09-01 | GSE1565 | GEO

ChIP-Seq analysis C57BL/6 thymocytes

Project description:In this study, we show that in addition to regulating DP thymocytes survival, RORgT also controls genes that regulate thymocyte migration, proliferation, and T cell receptor (TCR) selection. Strikingly, pharmacological inhibition of RORg skews TCR gene rearrangement, limits T cell repertoire diversity, and inhibits development of autoimmune encephalomyelitis. Thus, targeting RORgT not only inhibits Th17 cell development and function but also fundamentally alters thymic-emigrant recognition of self and foreign antigens.

2016-10-20 | GSE88916 | GEO

NPMâ??ALK permits the survival of thymic T cells with aberrant T cell receptor rearrangements enabling thymic escape and tumor development

Project description:We present evidence to support a new model of Anaplastic Large Cell Lymphoma (ALCL) pathogenesis in which the malignancy is initiated in early thymocytes, prior to TCR rearrangement which is bypassed in NPMâ??ALK transgenic mice following Notch1 expression. In support, we show that T cell receptor (TCR) rearrangements are aberrant in some human ALCL, yielding events that would not normally be permissive for survival during T cell development. However, a TCR is required for thymic egress and subsequent development of peripheral tumors in mice yet this TCR must be downâ??regulated for Tâ??cell lymphomagenesis. Children affected by ALCL may thus harbor lymphoma-initiating cells in the thymocyte population that seeds relapse after chemotherapy. comparative genomic hybridization data from 43 human Anaplastic Large Cell Lymphoma (ALCL) samples and control samples

2016-01-05 | E-GEOD-67131 | biostudies-arrayexpress

Gene expression analysis of thymocyte subsets

2011-08-10 | GSE31082 | GEO

Gene expression analysis of thymocyte subsets

Project description:Mouse thymocytes can be classified into four major subsets based on expression of CD4 and CD8 co-receptors. CD4-CD8- (double negative, DN) cells become CD4+CD8+ (double positive, DP) cells following productive T cell receptor (TCR) beta chain rearrangement. A small proportion of DP cells are selected through interaction of clonal TCRalpha/beta and MHC self peptide complex expressed on thymic stromal cells. DP cell expressing MHC class I-restricted TCR become CD4-CD8+ cells, which will finally differentiate into cytotoxic T cells, while MHC class II restricted selection generates CD4+CD8- helper lineage T cells. We used microarrays to identify genes important for thymocyte differentiation and lineage determination by profiling gene expression in different thymocyte subsets. Mouse thymocytes were divided into four subsets based on CD4, CD8a, and TCRb expression and purified by flw cytometry. FACS purified DN (CD4-CD8a-TCRb-), DP (CD4+CD8a+), CD4SP (CD4+CD8a-TCRbhi) and CD8SP (CD4-CD8a+TCRbhi) populations were lysed in Trizol, and provided to the Genomics Core Facility of the Memorial Sloan-Kettering Cancer Center (MSKCC) for quality control, quantification, reverse transcription, labeling and hybridization to MOE430A 2.0 microarray chips (Affymetrix). Arrays were scanned per the manufacturer’s specifications for the Affymetrix MOE430v2 chip.

2011-08-09 | E-GEOD-31082 | biostudies-arrayexpress

NPM‐ALK permits the survival of thymic T cells with aberrant T cell receptor rearrangements enabling thymic escape and tumor development

Project description:We present evidence to support a new model of Anaplastic Large Cell Lymphoma (ALCL) pathogenesis in which the malignancy is initiated in early thymocytes, prior to TCR rearrangement which is bypassed in NPM‐ALK transgenic mice following Notch1 expression. In support, we show that T cell receptor (TCR) rearrangements are aberrant in some human ALCL, yielding events that would not normally be permissive for survival during T cell development. However, a TCR is required for thymic egress and subsequent development of peripheral tumors in mice yet this TCR must be down‐regulated for T‐cell lymphomagenesis. Children affected by ALCL may thus harbor lymphoma-initiating cells in the thymocyte population that seeds relapse after chemotherapy.

2016-01-05 | GSE67131 | GEO

Impact of Jmjd3 and Utx histone demethylases on Histone H3 lysine 27 trimethylation (H3K27Me3) in mature CD4 SP thymocytes

Project description:While histone H3 lysine 27 trimethylation (H3K27Me3) is associated with gene silencing, whether H3K27Me3 demethylation affects transcription and cell differentiation in vivo has remained elusive. To investigate this, we conditionally inactivated the two H3K27Me3 demethylases, Jmjd3 and Utx, in non-dividing intrathymic CD4+ T cell precursors. We show that both enzymes redundantly promote H3K27Me3 removal at, and expression of, a specific subset of genes involved in terminal thymocyte differentiation, especially S1pr1, encoding a sphingosine-phosphate receptor required for thymocyte egress. Floxed alleles of the genes encoding Utx and Jmjd3 (Kdm6a and Kdm6b, respectively) were deleted in double positive (DP) thymocytes carrying a CD4 Cre transgene. Genome-wide H3K27Me3 ChipSeq was performed on (i) pre-selection (CD69lo) DP thymocytes from wild-type mice carrying an endogenous polyclonal TCR repertoire, (ii) mature (TCRhi CD24lo) CD4 SP thymocytes from wild type (Wt), Jmjd3KO, UtxKO and dKO mice carrying an endogenous polyclonal TCR repertoire and (iii) mature (Va2hi CD24lo) CD4 SP thymocytes from wild type and dKO mice carrying the OTII TCR transgene.

2015-09-02 | E-GEOD-70795 | biostudies-arrayexpress

An anti-silencer- and SATB1-dependent chromatin hub regulates Rag1 and Rag2 gene expression during thymocyte development

Project description:Rag1 and Rag2 gene expression in CD4+CD8+ double positive (DP) thymocytes depends on the activity of a distant anti-silencer element (ASE) that counteracts the activity of an intergenic silencer. However, the mechanistic basis for ASE activity is unknown. Here we show that the ASE physically interacts with the distant Rag1 and Rag2 gene promoters in DP thymocytes, bringing the two promoters together to form an active chromatin hub. Moreover, we show that the ASE functions as a classical enhancer that can potently activate these promoters in the absence of the silencer or other locus elements. In thymocytes lacking the chromatin organizer SATB1, we identified a partial defect in Tcra gene rearrangement that was associated with reduced expression of Rag1 and Rag2 at the DP stage. SATB1 binds to the ASE and Rag promoters, facilitating inclusion of Rag2 in the chromatin hub and the loading of RNA polymerase II to both the Rag1 and Rag2 promoters. Our results provide a novel framework for understanding ASE function and demonstrate a novel role for SATB1 as a regulator of Rag locus organization and gene expression in DP thymocytes. Sequencing of Satb1-ChIP and input control from 6 wk old thymus

2015-02-25 | E-GEOD-66248 | biostudies-arrayexpress

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