The splicing regulators TIA1 and TIAL1 are required for the expression of the DNA damage repair machinery during B cell lymphopoiesis

Osma-García, Inés C.; Capitan-Sobrino, Dunja; Mouysset, Maïlys; Aubert, Yann; Maloudi, Orlane; Turner, Martin; Díaz-Muñoz, Manuel D.

doi:10.1016/j.celrep.2022.111869

Cited by 10 publications

(11 citation statements)

References 82 publications

(119 reference statements)

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“…2g ). The binding sites of wildtype and overexpressed epitope-tagged TIAL1 viP-CLIP in liver and other organs are consistent with the previously studied RRE using electrophoretic mobility shift assays (EMSA) with purified human TIAL1 protein 18 .…”

Section: Resultssupporting

confidence: 86%

“…The binding of TIAL1 family proteins to RNA modulates several aspects of RNA metabolism in the nucleus and cytoplasm. For example, TIAL1 family proteins have been shown to interact with Pol II to regulate transcription 15 , to control alternative splicing of pre-mRNA 16 – 18 , and to regulate the stability and translation of mRNA by binding to untranslated regions 16 , 18 – 22 . Furthermore, the C-terminal glutamine-rich prion like domain (PrLD) has been shown to be essential in stress granules formation 23 .…”

Section: Introductionmentioning

confidence: 99%

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In vivo PAR-CLIP (viP-CLIP) of liver TIAL1 unveils targets regulating cholesterol synthesis and secretion

et al. 2023

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System-wide cross-linking and immunoprecipitation (CLIP) approaches have unveiled regulatory mechanisms of RNA-binding proteins (RBPs) mainly in cultured cells due to limitations in the cross-linking efficiency of tissues. Here, we describe viP-CLIP (in vivo PAR-CLIP), a method capable of identifying RBP targets in mammalian tissues, thereby facilitating the functional analysis of RBP-regulatory networks in vivo. We applied viP-CLIP to mouse livers and identified Insig2 and ApoB as prominent TIAL1 target transcripts, indicating an important role of TIAL1 in cholesterol synthesis and secretion. The functional relevance of these targets was confirmed by showing that TIAL1 influences their translation in hepatocytes. Mutant Tial1 mice exhibit altered cholesterol synthesis, APOB secretion and plasma cholesterol levels. Our results demonstrate that viP-CLIP can identify physiologically relevant RBP targets by finding a factor implicated in the negative feedback regulation of cholesterol biosynthesis.

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Section: Resultssupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

In vivo PAR-CLIP (viP-CLIP) of liver TIAL1 unveils targets regulating cholesterol synthesis and secretion

et al. 2023

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“…Despite this, we did not detect any changes in GC B-cell progression through the cell cycle. This finding suggested that, as in progenitor B cells [ 25 ], TIA1 and TIAL1 do not regulate the cell cycle in GC B cells. TIA1- and TIAL1-dependent regulation of the cell cycle might then be specific to the conditions and cell types analyzed.…”

Section: Discussionmentioning

confidence: 95%

“…TIA1 and TIAL1 deletion is embryonic lethal in mice [ 23 , 24 ]. They are needed for the repair of physiological DNA damage in developing B cells [ 25 ] and control p53 mRNA translation after mature B-cell activation with mitogens [ 26 ]. Here, we reveal the intrinsic role of TIA1 and TIAL1 in GC B cells, show that these RBPs are essential for the generation of high-affinity antibody responses, and identify Mcl1 as one of the key mRNA targets of TIA1 and TIAL1 that allows the selection and survival of antigen-specific GC B cells.…”

Section: Introductionmentioning

confidence: 99%

The RNA binding proteins TIA1 and TIAL1 promote Mcl1 mRNA translation to protect germinal center responses from apoptosis

et al. 2023

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Germinal centers (GCs) are essential for the establishment of long-lasting antibody responses. GC B cells rely on post-transcriptional RNA mechanisms to translate activation-associated transcriptional programs into functional changes in the cell proteome. However, the critical proteins driving these key mechanisms are still unknown. 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 prosurvival molecule MCL1. Thus, we demonstrate here that TIA1 and TIAL1 are key players in the post-transcriptional program that selects high-affinity antigen-specific GC B cells.

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“…It shows the capability to associate with distinct internal RNA elements, thereby enhancing the mRNA stability [ 40 , 41 ]. TIAL1, known as TIA1 Cytotoxic Granule Associated RNA Binding Protein Like 1, plays multifaceted roles, including its ability to enhance mRNA stability [ 42 , 43 ]. Taken together, our results revealed much higher frequencies of RBP bindings in negative m 6 A sequences than in positive sequences.…”

Section: Resultsmentioning

confidence: 99%

Understanding YTHDF2-mediated mRNA degradation by m6A-BERT-Deg

Zhang,

Jo,

Zhang

et al. 2024

Briefings in Bioinformatics

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N6-methyladenosine (m6A) is the most abundant mRNA modification within mammalian cells, holding pivotal significance in the regulation of mRNA stability, translation and splicing. Furthermore, it plays a critical role in the regulation of RNA degradation by primarily recruiting the YTHDF2 reader protein. However, the selective regulation of mRNA decay of the m6A-methylated mRNA through YTHDF2 binding is poorly understood. To improve our understanding, we developed m6A-BERT-Deg, a BERT model adapted for predicting YTHDF2-mediated degradation of m6A-methylated mRNAs. We meticulously assembled a high-quality training dataset by integrating multiple data sources for the HeLa cell line. To overcome the limitation of small training samples, we employed a pre-training-fine-tuning strategy by first performing a self-supervised pre-training of the model on 427 760 unlabeled m6A site sequences. The test results demonstrated the importance of this pre-training strategy in enabling m6A-BERT-Deg to outperform other benchmark models. We further conducted a comprehensive model interpretation and revealed a surprising finding that the presence of co-factors in proximity to m6A sites may disrupt YTHDF2-mediated mRNA degradation, subsequently enhancing mRNA stability. We also extended our analyses to the HEK293 cell line, shedding light on the context-dependent YTHDF2-mediated mRNA degradation.

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The splicing regulators TIA1 and TIAL1 are required for the expression of the DNA damage repair machinery during B cell lymphopoiesis

Cited by 10 publications

References 82 publications

In vivo PAR-CLIP (viP-CLIP) of liver TIAL1 unveils targets regulating cholesterol synthesis and secretion

In vivo PAR-CLIP (viP-CLIP) of liver TIAL1 unveils targets regulating cholesterol synthesis and secretion

The RNA binding proteins TIA1 and TIAL1 promote Mcl1 mRNA translation to protect germinal center responses from apoptosis

Understanding YTHDF2-mediated mRNA degradation by m6A-BERT-Deg

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