Memory T Cell RNA Rearrangement Programmed by Heterogeneous Nuclear Ribonucleoprotein hnRNPLL

Wu, Zuopeng; Jia, Xinying; Cruz, Laura de la; Su, Xun‐Cheng; Marzolf, Bruz; Troisch, Pamela; Zak, Daniel E.; Hamilton, Adam; Whittle, Belinda; Yu, Di; Sheahan, Daniel G.; Bertram, Edward M.; Aderem, Alan; Otting, Gottfried; Goodnow, Christopher C.; Hoyne, Gerard F.

doi:10.1016/j.immuni.2008.11.004

Cited by 71 publications

(130 citation statements)

References 51 publications

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“…Among these instances was the well-known example of Ptprc-ex6, and we rediscovered its regulation hnRPLL (10)(11)(12). The cell type distribution of this AS event seems to be shared with only a few other transcripts [of 134 candidate targets proposed in the work by Oberdoerffer et al (10) from transfection experiments and addressed by our analyses, none seemed to correlate with Ptprc-ex6 exclusion or Hnrpll expression], perhaps suggesting a dedicated mode of control of this essential modulator of lymphocyte activation (31).…”

Section: Discussionmentioning

confidence: 99%

“…This group included Ptprc_ex6 paired with Hnrpll. Because hnRPLL has been convincingly shown to regulate Ptprc splicing (10)(11)(12), this rediscovery through unsupervised analysis provided a measure of verification of the process.…”

Section: Canonical and Alternative Splice Sites Identified By Rna-seqmentioning

confidence: 99%

“…Other notable examples are the splicing of transcripts encoding adhesion molecules such as PECAM1 or CD44, which modulate cell-stroma interactions, or the extracellular domain of the coinhibitory molecule CTLA4 (9). A particularly well-studied example is CD45, with isoforms that are distinct in B and T lymphocytes and vary with the differentiation/activation state of the cell under the control of the splicing regulator hnRPLL (10)(11)(12). Despite these important roles that AS plays in immune cells, a comprehensive evaluation has not been done to assess the distribution and variation across different lineages of the immune system.…”

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confidence: 99%

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Differential splicing across immune system lineages

Ergün

Doran

Costello

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Alternative splicing (AS) allows increased diversity and orthogonal regulation of the transcriptional products of mammalian genomes. To assess the distribution and variation of alternative splicing across cell lineages of the immune system, we comprehensively analyzed RNA sequencing and microarray data generated by the Immunological Genome Project Consortium. AS is pervasive: 60% of genes showed frequent AS isoforms in T or B lymphocytes, with 7,599 previously unreported isoforms. Distinct cell specificity was observed, with differential exon skipping in 5% of genes otherwise coexpressed in both B and T cells. The distribution of isoforms was mostly all or none, suggesting on/off switching as a frequent mode of AS regulation in lymphocytes. From the identification of differential exon use in the microarray data, clustering of exon inclusion/exclusion patterns across all Immunological Genome Project cell types showed that ∼70% of AS exons are distributed along a common pattern linked to lineage differentiation and cell cycling. Other AS events distinguished myeloid from lymphoid cells or affected only a small set of exons without clear lineage specificity (e.g., Ptprc). Computational analysis predicted specific associations between AS exons and splicing regulators, which were verified by detection of the hnRPLL/ Ptprc connection.A lternative splicing (AS), the process of selectively including or removing exons to create a variety of transcripts from the same pre-mRNA, plays an important role in amplifying the diversity and flexibility of genome-encoded molecules (1, 2). AS can result in different protein isoforms or generate mRNAs of identical coding sequence but varying in their stability, localization, susceptibility to translational control, or microRNA regulation. AS is frequent and ubiquitous, affecting 55-95% of multiexon genes in mammals in different estimates (3-6). It is involved in a wide range of biological phenomena, ranging from sex determination to apoptosis or tumor formation. It also allows evolutionary tinkering with transcript structure and gradual transitions in gene function (7).Splicing events are overrepresented in genes involved in signaling and transcriptional regulation (receptors, signaling transduction, and transcription factors) and immune and nervous system processes. It has been hypothesized that alternative splicing is particularly valuable in complex systems, where information is processed differently at different times (immune response) or fine-tuning of signal integration is important (5). In the immune system, the first instance of AS recognized was the now textbook case of differential processing of primary Ig transcripts generating either a membrane receptor in naïve B cells or a secreted protein after antigen-induced differentiation (8). Other notable examples are the splicing of transcripts encoding adhesion molecules such as PECAM1 or CD44, which modulate cell-stroma interactions, or the extracellular domain of the coinhibitory molecule CTLA4 (9). A particularly well-studie...

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Section: Discussionmentioning

confidence: 99%

Section: Canonical and Alternative Splice Sites Identified By Rna-seqmentioning

confidence: 99%

mentioning

confidence: 99%

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Differential splicing across immune system lineages

Ergün

Doran

Costello

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…It is possible that hnRNP L and hnRNP LL may have overlapping functions, but with different mRNAbinding requirements. Alternatively, hnRNP L may be mediating the basal CD45 alternative splicing, whereas hnRNP LL may be necessary in cells that receive a TCR signal to induce exon skipping (46)(47)(48). Further investigation has to clarify the shared or specific role of both proteins in TCR signaling and CD45 alternative splicing.…”

Section: Discussionmentioning

confidence: 99%

Alternative Splicing Controlled by Heterogeneous Nuclear Ribonucleoprotein L Regulates Development, Proliferation, and Migration of Thymic Pre-T Cells

Gaudreau

Heyd

Bastien

et al. 2012

The Journal of Immunology

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The regulation of posttranscriptional modifications of pre-mRNA by alternative splicing is important for cellular function, development, and immunity. The receptor tyrosine phosphatase CD45, which is expressed on all hematopoietic cells, is known for its role in the development and activation of T cells. CD45 is known to be alternatively spliced, a process that is partially regulated by heterogeneous nuclear ribonucleoprotein (hnRNP) L. To investigate the role of hnRNP L further, we have generated conditional hnRNP L knockout mice and found that LckCre-mediated deletion of hnRNP L results in a decreased thymic cellularity caused by a partial block at the transition stage between double-negative 4 and double-positive cells. In addition, hnRNP L−/− thymocytes express aberrant levels of the CD45RA splice isoforms and show high levels of phosphorylated Lck at the activator tyrosine Y394, but lack phosphorylation of the inhibitory tyrosine Y505. This indicated an increased basal Lck activity and correlated with higher proliferation rates of double-negative 4 cells in hnRNP L−/− mice. Deletion of hnRNP L also blocked the migration and egress of single-positive thymocytes to peripheral lymphoid organs in response to sphingosine-1-phosphate and the chemokines CCL21 and CXCL12 very likely as a result of aberrant splicing of genes encoding GTPase regulators and proteins affecting cytoskeletal organization. Our results indicate that hnRNP L regulates T cell differentiation and migration by regulating pre-TCR and chemokine receptor signaling.

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“…hnRNPLL was identified through a targeted lentiviral shRNA screen for regulators of CD45RA to CD45RO switching during memory T-cell development (9) and independently through two separate screens performed by different groups for exclusion of CD45 exon 4 in a minigene context (10) and for altered CD44 and CD45R expression on T cells in N-ethyl-N-nitrosourea (ENU)-mutagenized mice (11). Mice with an ENU-induced mutant allele of Hnrpll (which encodes hnRNPLL) showed defects in T-cell survival and homeostasis (11). hnRNPLL is up-regulated during T-cell activation; it also is highly expressed in plasma cells, where it regulates the switching between membrane and secreted Ig in a plasma cell line (12).…”

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confidence: 99%

RNA-binding protein hnRNPLL regulates mRNA splicing and stability during B-cell to plasma-cell differentiation

Chang

Rao

2015

Proc. Natl. Acad. Sci. U.S.A.

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Posttranscriptional regulation is a major mechanism to rewire transcriptomes during differentiation. Heterogeneous nuclear RNA-binding protein LL (hnRNPLL) is specifically induced in terminally differentiated lymphocytes, including effector T cells and plasma cells. To study the molecular functions of hnRNPLL at a genomewide level, we identified hnRNPLL RNA targets and binding sites in plasma cells through integrated Photoactivatable-RibonucleosideEnhanced Cross-Linking and Immunoprecipitation (PAR-CLIP) and RNA sequencing. hnRNPLL preferentially recognizes CA dinucleotide-containing sequences in introns and 3′ untranslated regions (UTRs), promotes exon inclusion or exclusion in a context-dependent manner, and stabilizes mRNA when associated with 3′ UTRs. During differentiation of primary B cells to plasma cells, hnRNPLL mediates a genome-wide switch of RNA processing, resulting in loss of B-cell lymphoma 6 (Bcl6) expression and increased Ig productionboth hallmarks of plasma-cell maturation. Our data identify previously unknown functions of hnRNPLL in B-cell to plasma-cell differentiation and demonstrate that the RNA-binding protein hnRNPLL has a critical role in tuning transcriptomes of terminally differentiating B lymphocytes.

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Memory T Cell RNA Rearrangement Programmed by Heterogeneous Nuclear Ribonucleoprotein hnRNPLL

Cited by 71 publications

References 51 publications

Differential splicing across immune system lineages

Differential splicing across immune system lineages

Alternative Splicing Controlled by Heterogeneous Nuclear Ribonucleoprotein L Regulates Development, Proliferation, and Migration of Thymic Pre-T Cells

RNA-binding protein hnRNPLL regulates mRNA splicing and stability during B-cell to plasma-cell differentiation

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