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

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

doi:10.1038/s41423-023-01063-4

Cited by 4 publications

(3 citation statements)

References 68 publications

(86 reference statements)

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“…FUBP1-mediated up-regulation of MYC was reportedly due to increased transcription, but subsequent studies that either reduced or eliminated FUBP1 from cells have seen no effect on the level of MYC [ 37 , 38 ]. TIAR ( TIAL1 gene)–and possibly TIA1–regulation of MYC was through 3′UTR binding [ 35 ], but removal of TIA1 and TIAL1 genes in B cells did not alter MYC expression [ 39 ]. Comparatively, previous studies that have reduced HNRNPC expression have consistently shown reduced MYC expression [ 18 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of MYC intron 2 regions that modulate expression

Tompkins,

Xue,

Peterson

et al. 2024

PLoS ONE

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MYC pre-mRNA is spliced with high fidelity to produce the transcription factor known to regulate cellular differentiation, proliferation, apoptosis, and alternative splicing. The mechanisms underpinning the pre-mRNA splicing of MYC, however, remain mostly unexplored. In this study, we examined the interaction of heterogeneous nuclear ribonucleoprotein C (HNRNPC) with MYC intron 2. Building off published eCLIP studies, we confirmed this interaction with poly(U) regions in intron 2 of MYC and found that full binding is correlated with optimal protein production. The interaction appears to be compensatory, as mutational disruption of all three poly(U) regions was required to reduce both HNRNPC binding capacity and fidelity of either splicing or translation. Poly(U) sequences in MYC intron 2 were relatively conserved across sequences from several different species. Lastly, we identified a short sequence just upstream of an HNRNPC binding region that when removed enhances MYC translation.

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Section: Discussionmentioning

confidence: 99%

Identification of MYC intron 2 regions that modulate expression

Tompkins,

Xue,

Peterson

et al. 2024

PLoS ONE

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“…Interestingly. the study of B cells defective in splicing factors hnRNPF, HuR, PTBP1, TIA1 (Monzón-Casanova et al, 2018 ; Osma-Garcia et al, 2021 , 2023 ; Huang et al, 2023 ), and now hnRNPL, suggest that either MYC expression or its transcriptional program are especially sensitive to splicing defects in activated B cells. The activity of E2F transcription factors is also necessary for S-phase entry (Lam et al, 1998 ; Hsia et al, 2002 ; Nie et al, 2012 ; Hinman et al, 2009 ; Yusuf et al, 2004 ; Pae et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…RNA-binding proteins can modulate gene expression by affecting transcription, as well as by regulating the splicing and/or stability of the (pre)-mRNA transcripts, and thus have consequential cellular roles, including in B and other immune cells (Díaz-Muñoz and Turner, 2018 ; Turner and Díaz-Muñoz, 2018 ; Marasco and Kornblihtt, 2023 ). Splicing factors are emerging as important regulators of B cell biology, especially in activated B cells, with the consequent impact on the germinal center reaction (Qureshi et al, 2023 ; Monzón-Casanova et al, 2018 ; Diaz-Muñoz et al, 2015 ; Huang et al, 2023 ; Osma-Garcia et al, 2021 , 2023 ). hnRNPL belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family of RNA-binding proteins, composed of ~20 major, and some less abundant, members; many involved in splicing (Geuens et al, 2016 ; Han et al, 2010 ; Marasco and Kornblihtt, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Conserved role of hnRNPL in alternative splicing of epigenetic modifiers enables B cell activation

Subramani,

Fraszczak,

Helness

et al. 2024

EMBO Rep

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The multifunctional RNA-binding protein hnRNPL is implicated in antibody class switching but its broader function in B cells is unknown. Here, we show that hnRNPL is essential for B cell activation, germinal center formation, and antibody responses. Upon activation, hnRNPL-deficient B cells show proliferation defects and increased apoptosis. Comparative analysis of RNA-seq data from activated B cells and another eight hnRNPL-depleted cell types reveals common effects on MYC and E2F transcriptional programs required for proliferation. Notably, while individual gene expression changes are cell type specific, several alternative splicing events affecting histone modifiers like KDM6A and SIRT1, are conserved across cell types. Moreover, hnRNPL-deficient B cells show global changes in H3K27me3 and H3K9ac. Epigenetic dysregulation after hnRNPL loss could underlie differential gene expression and upregulation of lncRNAs, and explain common and cell type-specific phenotypes, such as dysfunctional mitochondria and ROS overproduction in mouse B cells. Thus, hnRNPL is essential for the resting-to-activated B cell transition by regulating transcriptional programs and metabolism, at least in part through the alternative splicing of several histone modifiers.

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Alternative splicing and related RNA binding proteins in human health and disease

Tao,

Zhang,

Wang

et al. 2024

Sig Transduct Target Ther

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Alternative splicing (AS) serves as a pivotal mechanism in transcriptional regulation, engendering transcript diversity, and modifications in protein structure and functionality. Across varying tissues, developmental stages, or under specific conditions, AS gives rise to distinct splice isoforms. This implies that these isoforms possess unique temporal and spatial roles, thereby associating AS with standard biological activities and diseases. Among these, AS-related RNA-binding proteins (RBPs) play an instrumental role in regulating alternative splicing events. Under physiological conditions, the diversity of proteins mediated by AS influences the structure, function, interaction, and localization of proteins, thereby participating in the differentiation and development of an array of tissues and organs. Under pathological conditions, alterations in AS are linked with various diseases, particularly cancer. These changes can lead to modifications in gene splicing patterns, culminating in changes or loss of protein functionality. For instance, in cancer, abnormalities in AS and RBPs may result in aberrant expression of cancer-associated genes, thereby promoting the onset and progression of tumors. AS and RBPs are also associated with numerous neurodegenerative diseases and autoimmune diseases. Consequently, the study of AS across different tissues holds significant value. This review provides a detailed account of the recent advancements in the study of alternative splicing and AS-related RNA-binding proteins in tissue development and diseases, which aids in deepening the understanding of gene expression complexity and offers new insights and methodologies for precision medicine.

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

Cited by 4 publications

References 68 publications

Identification of MYC intron 2 regions that modulate expression

Identification of MYC intron 2 regions that modulate expression

Conserved role of hnRNPL in alternative splicing of epigenetic modifiers enables B cell activation

Alternative splicing and related RNA binding proteins in human health and disease

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