Human U1 snRNA forms a new chromatin‐associated snRNP with TAF15

Jobert, Laure; Pinzón, Natalia; Herreweghe, Elodie Van; Jády, Beáta E.; Guialis, Apostolia; Kiss, Tamás; Tora, Làszlò

doi:10.1038/embor.2009.24

Cited by 53 publications

(43 citation statements)

References 18 publications

(24 reference statements)

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“…A similar process could also extend to anti-chromatin B cells in B6.NZBc13 mice. Although chromatin is a complex of DNA and histones that is recognized by DNA-sensing TLR9, it was recently shown to tightly associate with a complex of U1 RNA and another RNP, TAF15 [25]. As TLR3 and TLR9 are both sequestered in endosomes, chromatin-reactive B cells may also receive TLR3 signalling required for their activation and survival.…”

Section: Discussionmentioning

confidence: 99%

An intrinsic B‐cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice

et al. 2010

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Introgression of a New Zealand Black (NZB) chromosome 13 interval onto a C57BL/6 (B6) background (B6.NZBc13) is sufficient to produce many hallmarks of lupus, including hightitre anti-chromatin antibody production, abnormal B-and T-cell activation, and renal disease. In this study we sought to characterize the immune defects leading to these abnormalities. By generating hematopoietic chimeras and BCR transgenic mice, we show that the congenic autoimmune phenotype can be transferred by BM cells and requires the presence of autoreactive B cells. Using the hen egg white lysozyme immunoglobulin transgenic mouse model, we demonstrate that B-cell anergy, deletion, and receptor editing are intact. Nevertheless, congenic B cells exhibit altered peripheral B-cell selection, as demonstrated by enhanced survival and activation of endogenous B cells with autoreactivity to chromatin and Sm/ribonucleoprotein. Given the autoantibody specificities to nuclear antigens, TLR signalling was assessed. B6.NZBc13 B cells were hyper-responsive to poly(I:C), a TLR3 ligand, demonstrating enhanced proliferation and survival as compared to B6 B cells. Our findings indicate the presence of an intrinsic B-cell defect on NZB chromosome 13 that results in hyper-responsiveness to a dsRNA analogue and implicates its potential supporting role in the generation of autoimmunity in B6.NZBc13 mice. Keywords: Autoimmunity . B cells . TLRs Supporting Information available online IntroductionSystemic lupus erythematosus is a chronic autoimmune disorder characterized by the production of antibodies directed against nuclear antigens (ANAs). Similar to human lupus, the New Zealand Black (NZB) mouse produces antibodies directed against nuclear antigens, develops Coomb's positive hemolytic anaemia, and exhibits a number of phenotypic and functional B-cell abnormalities (reviewed in [1]). Although glomerulonephritis is mild in these mice, severe nephritis develops when the NZB background is crossed onto a permissive MHC haplotype (H-2 bm12 ), indicating that this mouse possesses a full complement of non-MHC lupus susceptibility genes [2].Generation of congenic mice, by introgression of homozygous chromosomal intervals from the NZB mouse strain onto a normal mouse C57BL/6 (B6) background, has been a particularly useful technique for characterizing susceptibility loci and their role in disease genesis [3]. In our mapping study of (B6 Â NZB) F 2 mice, we identified a locus on NZB chromosome (c) 13 that was linked to increased B-cell activation and abnormal IgM production [4]. To further characterize this locus, we generated congenic mice with an NZB c13 interval (denoted B6.NZBc13). B6.NZBc13 mice spontaneously developed autoimmunity characterized by hightitre IgM and IgG anti-chromatin antibody production, increased 527T-cell activation, expansion of DCs, and the development of mild glomerulonephritis [5]. Moreover, as predicted from our mapping study, B6.NZBc13 mice closely recapitulated the abnormal polyclonal B-cell activation and B-cell subset distribution...

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Section: Discussionmentioning

confidence: 99%

An intrinsic B‐cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice

et al. 2010

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“…fus could ride with RNA polymerase II and either directly interact with the 59 splice site and recruit U1-snRNP to the nascent pre-mRNA or recruit other splicing factors. In this context, it is interesting that TAF15 has been shown to interact with the RNA component of U1, which provides direct interaction with the 59 splice site (Jobert et al 2009). The finding that a fus-binding motif (GGUG) closely resembles a consensus 59 splice site (GGUG/A) suggests a possible direct interaction with the 59 splice site.…”

Section: Discussionmentioning

confidence: 99%

fus/TLS orchestrates splicing of developmental regulators during gastrulation

Dichmann

Harland²

2012

Genes Dev.

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Here we investigated the function of the atypical RNA-binding protein fus/TLS (fused in sarcoma/translocated in sarcoma) during early frog development. We found that fus is necessary for proper mRNA splicing of a set of developmental regulatory genes during early frog development and gastrulation. Upon fus knockdown, embryos fail to gastrulate and show mesodermal differentiation defects that we connect to intron retention in fgf8 (fibroblast growth factor 8) and fgfr2 (fgf receptor 2) transcripts. During gastrulation, the animal and marginal regions dissociate, and we show that this is caused, at least in part, by intron retention in cdh1 transcripts. We confirm the specificity of splicing defects at a genomic level using analysis of RNA sequencing (RNA-seq) and show that 3%-5% of all transcripts display intron retention throughout the pre-mRNA. By analyzing gene ontology slim annotations, we show that the affected genes are enriched for developmental regulators and therefore represent a biologically coherent set of targets for fus regulation in embryogenesis. This shows that fus is central to embryogenesis and may provide information on its function in neurodegenerative disease.[Keywords: Xenopus; fus; splicing; signaling; embryo development; RNA-seq] Supplemental material is available for this article. Pre-mRNA splicing, alternative and constitutive, is catalyzed by the spliceosome that contains five small nuclear ribonucleoproteins (snRNPs): U1, U2, U4, U5, and U6. Splicing occurs in a stepwise fashion, and a series of distinct complexes form in the process at the 59 and 39 splice sites and branch point site (Wahl et al. 2009). However, these sequences are short and poorly conserved. During splicing, the spliceosome must therefore succeed in recognizing and joining splice sites that are surrounded by numerous similar sequences and often separated by considerable distances. Further complicating the task, the interactions between the snRNPs and the pre-mRNA are generally weak and rely for specificity on numerous auxiliary proteins that interact with the core snRNPs. This general principle of multiple interactions is important not only for precisely finding correct splice pairs, but also for the flexibility necessary for alternative splice site selection.Comprehensive analysis of purified early spliceosomal complexes shows that they consist of at least 85 and perhaps as many as 150-300 different proteins with a combined mass of 2.7 MDa. Many of these function in the enzymatic and conformational changes that occur during splicing, while others are involved in exon and intron definition by binding to splicing enhancers or silencers present in the pre-mRNA. For example, members of the serine-arginine-rich splice factors (SR proteins) frequently bind sequences in exons and stimulate exon inclusion by stabilizing U1 and U2 binding to the 59 splice site and branch point site, respectively. Other well-known splicing regulators are the heterologous nuclear RNPs (hnRNPs) that generally repress exon inclusion and hence co...

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“…Recently, we showed that a chromatin-associated fraction of TAF15 associates with a human U1 small nuclear RNA. 8 Thus, we hypothesized that the U1-TAF15 particle is produced by remodeling of the canonical U1-snRNP, further suggesting a possible role of TAF15 in additional steps of RNA metabolism. Moreover, an interesting link between FET proteins and miRNAs has emerged.…”

Section: Taf15 (Formerly Tafmentioning

confidence: 99%

TAF15 is important for cellular proliferation and regulates the expression of a subset of cell cycle genes through miRNAs

et al. 2012

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1TAF15 (formerly TAFII68) is a member of the FET (FUS, EWS, TAF15) family of RNA-and DNA-binding proteins whose genes are frequently translocated in sarcomas. By performing global gene expression profiling, we found that TAF15 knockdown affects the expression of a large subset of genes, of which a significant percentage is involved in cell cycle and cell death. In agreement, TAF15 depletion had a growth-inhibitory effect and resulted in increased apoptosis. Among the TAF15-regulated genes, targets of microRNAs (miRNAs) generated from the onco-miR-17 locus were overrepresented, with CDKN1A/p21 being the top miRNAstargeted gene. Interestingly, the levels of onco-miR-17 locus coded miRNAs (miR-17-5p and miR-20a) were decreased upon TAF15 depletion and shown to affect the post-transcriptional regulation of TAF15-dependent genes, such as CDKN1A/p21. Thus, our results demonstrate that TAF15 is required to regulate gene expression of cell cycle regulatory genes post-transcriptionally through a pathway involving miRNAs. The findings that high TAF15 levels are needed for rapid cellular proliferation and that endogenous TAF15 levels decrease during differentiation strongly suggest that TAF15 is a key regulator of maintaining a highly proliferative rate of cellular homeostasis.Oncogene ( Keywords: FUS/EWS/TAF15 (FET) proteins; miRNAs; transcription; proliferation; neuronal differentiation; neuroblastoma INTRODUCTION TAF15 (formerly TAF II 68) is a nuclear protein known to associate with a distinct subpopulation of transcription factor IID (TFIID), a multi-subunit complex that nucleates the pre-initiation complex on the promoters of on protein-coding genes.1,2 As TAF15 was not found to be associated with all human TFIID complexes and has no ortholog in other non-vertebrate species, TAF15 is not considered a canonical TAF.3 TAF15 harbors a transcriptional activation domain, a RNA recognition motif and many Arg-Gly-Gly (RGG) repeats known to participate in RNA binding.1 TAF15 together with the related FUS and EWS constitutes the FET (FUS/EWS/TAF15) protein family whose genes are frequently translocated in sarcomas and rare hematopoietic and epithelial cancers. 4 In each case, the N-terminus of the proteins, containing a potent transcriptional activation domain, 5 is fused to the DNA-binding domain of a transcription factor to form oncogenic chimeras.

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Human U1 snRNA forms a new chromatin‐associated snRNP with TAF15

Cited by 53 publications

References 18 publications

An intrinsic B‐cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice

An intrinsic B‐cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice

fus/TLS orchestrates splicing of developmental regulators during gastrulation

TAF15 is important for cellular proliferation and regulates the expression of a subset of cell cycle genes through miRNAs

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