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Regulation of CD8 T Cell Differentiation by the RNA-Binding Protein DDX5.

ABSTRACT: The RNA-binding protein DEAD-box protein 5 (DDX5) is a polyfunctional regulator of gene expression, but its role in CD8+ T cell biology has not been extensively investigated. In this study, we demonstrate that deletion of DDX5 in murine CD8+ T cells reduced the differentiation of terminal effector, effector memory T, and terminal effector memory cells while increasing the generation of central memory T cells, whereas forced expression of DDX5 elicited the opposite phenotype. DDX5-deficient CD8+ T cells exhibited increased expression of genes that promote central memory T cell differentiation, including Tcf7 and Eomes. Taken together, these findings reveal a role for DDX5 in regulating the differentiation of effector and memory CD8+ T cell subsets in response to microbial infection.

SUBMITTER: Louis TL

PROVIDER: S-EPMC10373580 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Regulation of CD8 T Cell Differentiation by the RNA-Binding Protein DDX5.

Louis Tiani L TL Wong William H WH Yao Priscilla P Kurd Nadia S NS Tysl Tiffani T Indralingam Cynthia S CS Ma Shengyun S Huang Wendy Jia Men WJM Chang John T JT

Journal of immunology (Baltimore, Md. : 1950) 20230701 2

The RNA-binding protein DEAD-box protein 5 (DDX5) is a polyfunctional regulator of gene expression, but its role in CD8+ T cell biology has not been extensively investigated. In this study, we demonstrate that deletion of DDX5 in murine CD8+ T cells reduced the differentiation of terminal effector, effector memory T, and terminal effector memory cells while increasing the generation of central memory T cells, whereas forced expression of DDX5 elicited the opposite phenotype. DDX5-deficient CD8+ ...[more]

PMID: 37265401

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Regulation of CD8 T cell differentiation by the RNA-binding protein DDX5

Project description:The RNA-binding protein DDX5 is a polyfunctional regulator of gene expression, but its role in CD8+ T cell biology has not been extensively investigated. In this study, we demonstrate that deletion of DDX5 reduced differentiation of terminal effector (TE), effector memory (TEM), and terminal effector memory (t-TEM) cells while increasing the generation of central memory (TCM) cells; forced expression of DDX5 elicited the opposite phenotype. DDX5-deficient CD8+ T cells exhibited increased expression of genes that promote TCM cell differentiation, including Tcf7 and Eomes. Together, these findings reveal a role for DDX5 in regulating the differentiation of effector and memory CD8+ T cell subsets in response to microbial infection.

2023-05-23 | GSE230028 | GEO

Regulation of CD8 T cell differentiation by the RNA-binding protein DDX5

Project description:Regulation of CD8 T cell differentiation by the RNA-binding protein DDX5

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Regulation of B cell differentiation by the ubiquitin-binding protein TAX1BP1.

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RNA binding protein DDX5 directs tuft cell specification and function to regulate microbial repertoire and disease susceptibility in the intestine.

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Early transcriptional and epigenetic regulation of CD8<sup>+</sup> T cell differentiation revealed by single-cell RNA sequencing.

Project description:During microbial infection, responding CD8+ T lymphocytes differentiate into heterogeneous subsets that together provide immediate and durable protection. To elucidate the dynamic transcriptional changes that underlie this process, we applied a single-cell RNA-sequencing approach and analyzed individual CD8+ T lymphocytes sequentially throughout the course of a viral infection in vivo. Our analyses revealed a striking transcriptional divergence among cells that had undergone their first division and identified previously unknown molecular determinants that controlled the fate specification of CD8+ T lymphocytes. Our findings suggest a model for the differentiation of terminal effector cells initiated by an early burst of transcriptional activity and subsequently refined by epigenetic silencing of transcripts associated with memory lymphocytes, which highlights the power and necessity of single-cell approaches.

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Musashi1 RNA-binding protein regulates oligodendrocyte lineage cell differentiation and survival.

Project description:Expression of Musashi1 (Msi1), an evolutionarily conserved RNA-binding protein, in neural stem cells of the subventricular zone in the postnatal and adult CNS indicates a potential role in the generation of oligodendrocytes. We now show Msi1 expression in a subset of oligodendrocyte progenitor (OP) cells in white matter areas temporally and spatially associated with oligodendrogenesis in the postnatal CNS. Msi1 function was evaluated by infection of OP cells with retroviral transduction of Msi1 or knockdown of endogenous Msi1. Retroviral expression of Msi1 significantly reduced the proportion of mature oligodendrocytes generated from OP cells in vitro and in vivo during myelination. Msi1 transduction also promoted OP survival, particularly under conditions of challenge from oxidative stress, while Msi1 siRNA knockdown resulted in dramatic OP cell death. Furthermore, in experimental demyelination Msi1 expression was increased among cells associated with lesions, including OP cells, indicating a potential role in the generation of remyelinating oligodendrocytes.

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CDX2 regulation by the RNA-binding protein MEX3A: impact on intestinal differentiation and stemness.

Project description:The homeobox transcription factor CDX2 plays a crucial role in intestinal cell fate specification, both during normal development and in tumorigenic processes involving intestinal reprogramming. The CDX2 regulatory network is intricate, but it has not yet been fully uncovered. Through genome-wide screening of a 3D culture system, the RNA-binding protein MEX3A was identified as putatively involved in CDX2 regulation; therefore, its biological relevance was addressed by setting up cell-based assays together with expression studies in murine intestine. We demonstrate here that MEX3A has a repressive function by controlling CDX2 levels in gastric and colorectal cellular models. This is dependent on the interaction with a specific binding determinant present in CDX2 mRNA 3'untranslated region. We have further determined that MEX3A impairs intestinal differentiation and cellular polarization, affects cell cycle progression and promotes increased expression of intestinal stem cell markers, namely LGR5, BMI1 and MSI1. Finally, we show that MEX3A is expressed in mouse intestine, supporting an in vivo context for interaction with CDX2 and modulation of stem cell properties. Therefore, we describe a novel CDX2 post-transcriptional regulatory mechanism, through the RNA-binding protein MEX3A, with a major impact in intestinal differentiation, polarity and stemness, likely contributing to intestinal homeostasis and carcinogenesis.

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RNA helicases DDX5 and DDX17 dynamically orchestrate transcription, microRNA and splicing programs in cell differentiation

Project description:RNA helicases DDX5 and DDX17 are members of a large family of highly conserved proteins involved in gene expression regulation, although their in vivo targets and activities in biological processes like cell differentiation, that requires reprogramming of gene expression programs at multiple levels, are not well characterized. In this report, we uncovered a new mechanism by which DDX5 and DDX17 cooperate with hnRNP H/F splicing factors to define epithelial- and myoblast-specific splicing subprograms. We next observed that downregulation of DDX5 and DDX17 protein expression during epithelial to mesenchymal transdifferentiation and during myogenesis contributes to switching splicing programs during these processes. Remarkably, this downregulation is mediated by the production of microRNAs induced upon differentiation in a DDX5/DDX17-dependent manner. Since DDX5 and DDX17 also function as coregulators of master transcriptional regulators of differentiation, we propose to name these proteins “master orchestrators” of differentiation, that dynamically orchestrate several layers of gene expression. 6 samples of MCF7 cells exposed to different treatments were analyzed: 3 x siCTRL ; 3 x si(DDX5-17) AND 6 samples of MCF10 cells exposed to different treatments were analyzed: 3 x siCTRL ; 3 x si(DDX5-17)

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Regulation of monocyte induced cell migration by the RNA binding protein, FXR1.

Project description:FXR1 belongs to a family of RNA-binding proteins that play critical roles in post-transcriptional regulation of gene expression in immunity, development and cancer. FXR1 is associated with regulation of specific mRNAs in myocytes and macrophages. In quiescent cells (> 24 h of extended serum-starvation, ∼30-48 h or more), a spliced isoform of FXR1, FXR1a, promotes translation of the cytokine TNFα, independent of the effects of RNA levels. Here we examined the role of FXR1 in THP1 human monocytic leukemic cells that were grown in serum, as well as in early (24 h) serum-starvation conditions that demonstrates differences in gene expression mechanisms and is distinct from quiescent (> 24 h extended serum-starvation) cells. Global RNA profiling, conducted to investigate the role of FXR1 on mRNA levels, revealed that FXR1 affects levels of specific mRNAs in serum-grown and in early 24 h serum-starvation conditions. FXR1 decreases levels of several mRNAs, including as previously identified, CDKN1A (p21CIP1 or p21) mRNA in serum-grown cells. Interestingly, we find that FXR1 positively regulates mRNA levels of specific cytokines and chemokines in serum-grown and in early 24 h serum-starvation conditions. These include IL1β and CCL2 that control cell migration. Accordingly, depletion and overexpression of FXR1 decreased and increased levels of CCL2 mRNA. Consistent with the reduced levels of IL1β, CCL2 and other chemokines upon FXR1 depletion, our data reveal that depletion of FXR1 decreases the ability of these cells to induce cell migration of neighboring monocytic cells. These data reveal a new role of FXR1 in controlling induction of monocyte migration.

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