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The RNA binding proteins TIA1 and TIAL1 protect germinal centre responses from apoptosis [iCLIP]

ABSTRACT: Germinal centres (GC) are essential for the establishment of long-lasting antibody responses. In there, GC B cells rely on post-transcriptional RNA mechanisms for translating activation-associated transcriptional programs into functional changes in the cell proteome. However, we still lack knowledge about which are the critical proteins driving these key mechanisms. Here we show that the RNA binding proteins TIA1 and TIAL1 are required for the generation of long-lasting GC responses. TIA1 and TIAL1- deficient GC B cells fail to undergo antigen-mediated positive selection, expansion and differentiation into B cell clones producing high-affinity antibodies. Mechanistically, TIA1 and TIAL1 control the transcriptional identity of dark and light zone GC B cells and enable timely expression of the pro-survival molecule MCL1. Altogether, we demonstrate here that TIA1 and TIAL1 are key players in the post-transcriptional program that selects high-affinity antigen-specific GC B cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE235655 | GEO | 2023/08/29

REPOSITORIES: GEO

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The RNA binding proteins TIA1 and TIAL1 protect germinal centre responses from apoptosis

Project description:Germinal centres (GC) are essential for the establishment of long-lasting antibody responses. In there, GC B cells rely on post-transcriptional RNA mechanisms for translating activation-associated transcriptional programs into functional changes in the cell proteome. However, we still lack knowledge about which are the critical proteins driving these key mechanisms. Here we show that the RNA binding proteins TIA1 and TIAL1 are required for the generation of long-lasting GC responses. TIA1 and TIAL1- deficient GC B cells fail to undergo antigen- mediated positive selection, expansion and differentiation into B cell clones producing high-affinity antibodies. Mechanistically, TIA1 and TIAL1 control the transcriptional identity of dark and light zone GC B cells and enable timely expression of the pro-survival molecule MCL1. Altogether, we demonstrate here that TIA1 and TIAL1 are key players in the post-transcriptional program that selects high-affinity antigen-specific GC B cells.

2023-08-29 | GSE235358 | GEO

CLIP-Seq of human to identify the global RNA binding sites for TIA1 and TIAL1 proteins

Project description:Individual nucleotide resolution UV-crosslinking and immunoprecipitation (iCLIP) and individual nucleotide resolution UV-crosslinking and affinity purification (iCLAP) were used to identify the global RNA binding sites for TIA1 and TIAL1 proteins. HeLa cells were UV crosslinked before lysing and digested with DNase and low concentration of RNase I. The protein-RNA complex were either immunoprecipitated with specific antibodies against either TIA1 or TIAL1 proteins and ligated to 3 prime adapter before separated by SDS-PAGE. For iCLAP, the His/Strep tagged proteins were overexpressed in HeLa cells, and the protein-RNA complexes were purified via Strep and His tag affinity purification. The proteins were digested by proteinase K and the RNA was reverse transcribed and self-circularised. The cDNA library was prepared by PCR with solexa primers compatible for high-throughput sequencing. This method allowed specific identify of crosslinked nucleotides, and genome-wide targets for TIA1 and TIAL1 not identified before. This method also allowed comparison between the 2 homologous proteins, whose binding sites and functions could be redundent. iCLAP provided an independent way to validate the binding sites identified by iCLIP, since no antibody was used in the iCLAP method.

2011-07-28 | E-MTAB-432 | biostudies-arrayexpress

The RNA-binding proteins TIA1 and TIAL1 are required for the expression of the DNA damage repair machinery during B cell lymphopoiesis.

Project description:B-cell lymphopoiesis requires dynamic modulation of the B-cell transcriptome at the post-transcriptional level, although the implication of RNA binding proteins (RBPs) remain largely unknown. Here we show that the RBPs TIA1 and TIAL1 are essential in B cells and, if deleted, there is a developmental block at the pro-B cell stage. TIA1 and TIAL1 have redundant functions. They act together as global splicing regulators for the expression of mRNAs including those involved in DNA damage repair in pro-B cells. Mechanistically, TIA1 and TIAL1 bind to 5’splice sites for exon definition, splicing and expression of DNA damage sensors like Chek2 and Rif1. In their absence, pro-B cells show exacerbated DNA damage, altered P53 expression and increased cell death. Altogether, our study uncovers the importance of tight regulation of mRNA splicing by TIA1 and TIAL1 for the expression of integrative transcriptional programs for DNA damage sensing and repair during B-cell development.

2022-12-20 | GSE186701 | GEO

The RNA-binding proteins TIA1 and TIAL1 are required for the expression of the DNA damage repair machinery during B cell lymphopoiesis

Project description:B-cell lymphopoiesis requires dynamic modulation of the B-cell transcriptome at the post-transcriptional level, although the implication of RNA-binding proteins (RBPs) remain largely unknown. Here we show that the RBPs TIA1 and TIAL1 are essential in B cells and, if deleted, there is a developmental block at the pro-B cell stage. TIA1 and TIAL1 have redundant functions. They act together as global splicing regulators for the expression of mRNAs including those involved in DNA damage repair in pro-B cells. Mechanistically, TIA1 and TIAL1 bind to 5’splice sites for exon definition, splicing and expression of DNA damage sensors like Chek2 and Rif1. In their absence, pro-B cells show exacerbated DNA damage, altered P53 expression and increased cell death. Altogether, our study uncovers the importance of tight regulation of mRNA splicing by TIA1 and TIAL1 for the expression of integrative transcriptional programs for DNA damage sensing and repair during B-cell development.

2022-12-20 | GSE188556 | GEO

iCLIP and iCLAP for TIA1 and TIAL1 proteins

Project description:iCLIP and iCLAP for TIA1 and TIAL1 proteins

| PRJEB2628 | ENA

TIA1 interactome from mouse cortex

Project description:The purpose of this experiment was to characterize the network of proteins that interact with TIA1, and to investigate whether tau exerts control over TIA1 protein interactions, TIA1 was immunoprecipitated from cortical brain tissue of 10 month-old WT (C57BL/6J), tau-/- and TIA1-/- mice. The specificity of the TIA1 IP was verified by immunoblotting with anti-TIA1 antibody (Fig. 3A), and the resulting TIA1 proteome was examined by mass spectrometry.

2018-10-26 | PXD003922 | Pride

Transcriptome-wide analysis links the short-term expression of the b isoforms of T-cell intracellular antigens to protective proteostasis-mediated survival and quiescence

Project description:Control of gene expression depends on genetics and environmental factors. The T-cell intracellular antigens T-cell intracellular antigen 1 (TIA1), TIA1-like/related protein (TIAL1/TIAR) and human antigen R (HuR/ELAVL1) are RNA-binding proteins that play crucial roles in regulating gene expression in both situations. This study used massive sequencing analysis to uncover molecular and functional mechanisms resulting from the short-time expression of the b isoforms of TIA1 and TIAR and HuR in HEK293 cells.

2018-11-22 | GSE113330 | GEO

Dynamic changes in E protein activity orchestrate germinal center and plasma cell development [ChIP-Seq]

Project description:Humoral immunity requires the generation of high-affinity antibodies, which involves the generation of germinal centres (GC) promoting class switch and affinity maturation of antigen-specific B cells, and the differentiation of long-lived plasma cells. This multi-layered process is tightly controlled by the activity of a transcriptional network including Bcl6, essential for the development of GC, and Blimp1, required for the differentiation of plasma cells. Here, we reveal an additional layer of complexity by demonstrating that dynamic changes in E-protein activity mediated by Id3 govern both GC and plasma cell differentiation. We show that down-regulation of Id3 expression in B cells in essential for releasing E2A and E2-2, the combined activity of which is required for both GC B cell and plasma cell differentiation. We demonstrate that this pathway controls the expression of multiple key factors required for antigen-induced B cell differentiation, including Blimp1, Xbp1, Mef2b and CXCR4 and is therefore critical for establishing the transcriptional network that controls GC B cell and plasma cell differentiation. Genome binding of transcription factor E2A

2016-05-13 | E-GEOD-72828 | biostudies-arrayexpress

Dynamic changes in E protein activity orchestrate germinal center and plasma cell development [RNA-Seq]

2016-05-13 | E-GEOD-72831 | biostudies-arrayexpress

Comparative gene expression profiles of T-dependent and T-independent germinal centre B cells in mice

Project description:Selection of B cells subjected to hypermutation in germinal centres (GC) during T-dependent (TD) antibody responses yields memory cells and long-lived plasma cells that produce high affinity antibodies biased to foreign antigens rather than self-antigens. GC also form in T-independent (TI) responses to polysaccharide antigens but failed selection results in GC involution and memory cells are not generated. To date there are no markers that allow phenotypic distinction of T-dependent and T-independent germinal centre B cells. We have now compared the global gene expression of GC B cells purified from mice immunized with either TD or TI antigens and identified eighty genes that are differentially expressed in TD GC. Keywords: T-dependent and T-independent germinal center B cells

2007-09-05 | GSE8906 | GEO

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