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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE188556 | GEO | 2022/12/20

REPOSITORIES: GEO

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Project description:During cell stress, the transcription and translation of immediate early genes are prioritized, while most other mRNAs are stored away in stress granules or degraded in P-bodies. TIA-1 is an mRNA binding protein that needs to translocate from the nucleus to seed the formation of stress granules in the cytoplasm. Since other stress granule components such as TDP-43, FUS, ATXN2, SMN, MAPT, HNRNPA2B1 and HNRNPA1 are crucial for the motor neuron diseases ALS / SMA and for the frontotemporal dementia FTD, here we studied mouse nervous tissue to identify mRNAs with selective dependence on Tia1 deletion. Transcriptome profiling with oligonucleotide microarrays in comparison of spinal cord and cerebellum, together with independent validation in quantitative reverse transcriptase PCR and immunoblots demonstrated several strong and consistent dysregulations. In agreement with previously reported TIA1 knock-down effects, cell cycle and apoptosis regulators were affected markedly with expression changes up to 2-fold, exhibiting increased levels for Cdkn1a, Ccnf, and Tprkb versus decreased levels for Bid and Inca1 transcripts. Novel and surprisingly strong expression alterations were detected for fat storage and membrane trafficking factors, with prominent above 3-fold upregulations of Plin4, Wdfy1, Tbc1d24, and Pnpla2, versus a 0.5 -fold?? downregulation of Cntn4 transcript, encoding an axonal membrane adhesion factor with established haploinsufficiency. In comparison subtle effects on the RNA processing machinery included up to 1.2-fold upregulations of Dcp1b and Tial1. The effect on lipid dynamics factors is noteworthy, since also the gene deletion of Tardbp (encoding TDP-43) and Atxn2 led to fat metabolism phenotypes in mouse. In conclusion, genetic ablation of the stress granule nucleator TIA-1 has a novel major effect on mRNAs encoding lipid homeostasis factors in the brain. Factorial design comparing Tia1 knock-out mice with wild type littermates in four different tissues (midbrain, cerebellum, liver, spinal cord) and 2 different ages.

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

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