The RNA helicase DDX17 controls the transcriptional activity of REST and the expression of proneural microRNAs in neuronal differentiation

Lambert, Marie-Pierre; Terrone, Sophie; Giraud, Guillaume; Benoit‐Pilven, Clara; Cluet, David; Combaret, Valérie; Mortreux, Franck; Auboeuf, Didier; Bourgeois, Cyril F.

doi:10.1093/nar/gky545

Cited by 49 publications

(53 citation statements)

References 78 publications

(95 reference statements)

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“…We performed RNA-seq analyses on 293T-LTR-GFP cells transiently transfected with a Tax expression vector. We then identified Tax-induced changes in gene expression level and in alternative splicing and annotated them as previously described 22,23 (Supplementary Data 1 and 2). Notably, the ectopic expression of Tax affected the splicing and gene expression levels of 939 and 523 genes, respectively (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Tax-mediated effects on splicing depend on DDX5/17. To estimate the role of DDX17 in Tax-regulated splicing events, RNA-sequencing was performed using 293T-LTR-GFP cells expressing or not Tax and depleted or not for DDX17 and its paralog DDX5, which cross-regulate and complement each other 22,33,34 . Tax had no effect on the expression of DDX5 and DDX17 (Figs.…”

Section: Resultsmentioning

confidence: 99%

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Intragenic recruitment of NF-κB drives splicing modifications upon activation by the oncogene Tax of HTLV-1

et al. 2020

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Chronic NF-κB activation in inflammation and cancer has long been linked to persistent activation of NF-κB-responsive gene promoters. However, NF-κB factors also massively bind to gene bodies. Here, we demonstrate that recruitment of the NF-κB factor RELA to intragenic regions regulates alternative splicing upon NF-κB activation by the viral oncogene Tax of HTLV-1. Integrative analyses of RNA splicing and chromatin occupancy, combined with chromatin tethering assays, demonstrate that DNA-bound RELA interacts with and recruits the splicing regulator DDX17, in an NF-κB activation-dependent manner. This leads to alternative splicing of target exons due to the RNA helicase activity of DDX17. Similar results were obtained upon Tax-independent NF-κB activation, indicating that Tax likely exacerbates a physiological process where RELA provides splice target specificity. Collectively, our results demonstrate a physical and direct involvement of NF-κB in alternative splicing regulation, which significantly revisits our knowledge of HTLV-1 pathogenesis and other NF-κB-related diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Intragenic recruitment of NF-κB drives splicing modifications upon activation by the oncogene Tax of HTLV-1

et al. 2020

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“…Among the many miRNAs known to participate in neuron development, the miR-26 family (miR-26a-1, miR-26a-2 and miR-26b) have a known role in tissue growth and differentiation, with regulated expression during development and tumorigenesis (Gao and Liu, 2011). In the nervous system, miR-26a is highly expressed in the mouse cerebral cortex at embryonic day 12 and throughout cortical development, where it has been shown to regulate neural progenitor differentiation and cell-cycle progression (Lambert et al, 2018;Zhang et al, 2018). Beyond this role in differentiation, the knocking down of miR-26a in peripheral sensory neurons led to impaired axon regeneration (Jiang et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal regulation of GSK3β levels by miRNA-26a controls axon development in cortical neurons

et al. 2020

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Both the establishment of neuronal polarity and axonal growth are crucial steps in the development of the nervous system. The local translation of mRNAs in the axon provides precise regulation of protein expression, and is now known to participate in axon development, pathfinding and synaptic formation and function. We have investigated the role of miR-26a in early stage mouse primary cortical neuron development. We show that micro-RNA-26a-5p (miR-26a) is highly expressed in neuronal cultures, and regulates both neuronal polarity and axon growth. Using compartmentalised microfluidic neuronal cultures, we identified a local role for miR-26a in the axon, where the repression of local synthesis of GSK3β controls axon development and growth. Removal of this repression in the axon triggers local translation of GSK3β protein and subsequent transport to the soma, where it can impact axonal growth. These results demonstrate how the axonal miR-26a can regulate local protein translation in the axon to facilitate retrograde communication to the soma and amplify neuronal responses, in a mechanism that influences axon development.

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“…DEADbox proteins are necessary for proper function of RNA in many cellular processes (Cordin et al, 2006;Fuller-Pace, 2013b;Gustafson and Wessel, 2010;Janknecht, 2010;Jarmoskaite and Russell, 2011). DDX17 and its close homolog DDX5 play an important role in various contexts, including processing of primary microRNA transcripts (pri-miRs) in the nucleus (Kao et al, 2019;Li et al, 2017;Mori et al, 2014), pre-mRNA alternative splicing Hö nig et al, 2002), ribosome biogenesis (Jalal et al, 2007), mRNA export (Montpetit et al, 2011), and coregulation of transcription Fuller-Pace, 2013a;Lambert et al, 2018;Samaan et al, 2014). DDX17 has also been implicated in immunity by affecting viral infectivity (Lorgeoux et al, 2013;Moy et al, 2014;Sithole et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

RNA Specificity and Autoregulation of DDX17, a Modulator of MicroRNA Biogenesis

2019

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Graphical Abstract Highlights d Crystal structures of human DDX17 core domains in multiple states are determined d DDX17 core domains exhibit RNA sequence preference via the RMFQ motif d DDX17 can enhance processing of pri-miRs by remodeling the 3 0 flanking region d N-terminal tail of DDX17 can regulate the ATPase activity In Brief Ngo et al. reveal crystal structures of DEAD-box 17 (DDX17) and show that the core catalytic domains recognize RNA sequence motifs in primary transcripts of microRNAs, to regulate processing by Drosha. DDX17 also has a unique N-terminal tail that can attenuate the ATPase activity. SUMMARY DDX17, a DEAD-box ATPase, is a multifunctional helicase important for various RNA functions, including microRNA maturation. Key questions for DDX17 include how it recognizes target RNAs and influences their structures, as well as how its ATPase activity may be regulated. Through crystal structures and biochemical assays, we show the ability of the core catalytic domains of DDX17 to recognize specific sequences in target RNAs. The RNA sequence preference of the catalytic core is critical for DDX17 to directly bind and remodel a specific region of primary microRNAs 3 0 to the mature sequence, and consequently enhance processing by Drosha. Furthermore, we identify an intramolecular interaction between the N-terminal tail and the DEAD domain of DDX17 to have an autoregulatory role in controlling the ATPase activity. Thus, we provide the molecular basis for how cognate RNA recognition and functional outcomes are linked for DDX17. À . We identify several mutations of DDX17 that affect ATP 4024 Cell Reports 29, 4024-4035, December 17, 2019 ª 2019 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). domains. STAR+METHODSDetailed methods are provided in the online version of this paper and include the following:TABLE d LEAD CONTACT AND MATERIALS AVAILABILITY d EXPERIMENTAL MODEL AND SUBJECT DETAILS d METHOD DETAILS B Materials B in vitro RNA transcription and purification B Protein purification B RNA Unwinding Assay B Size-exclusion chromatography-Multiangle light scattering B Electrophoretic Mobility Shift Assay B in vitro ATP hydrolysis Assay B Differential Scanning Fluorimetry B Crystallization and Data Collection B Structure determination and refinement B in vitro pri-miR processing assays B Hydroxyl radical footprinting B Selective hydroxyl acylation followed by primer extension (SHAPE) B Cell Culture and quantitative real-time PCR (qPCR)

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The RNA helicase DDX17 controls the transcriptional activity of REST and the expression of proneural microRNAs in neuronal differentiation

Cited by 49 publications

References 78 publications

Intragenic recruitment of NF-κB drives splicing modifications upon activation by the oncogene Tax of HTLV-1

Intragenic recruitment of NF-κB drives splicing modifications upon activation by the oncogene Tax of HTLV-1

Spatiotemporal regulation of GSK3β levels by miRNA-26a controls axon development in cortical neurons

RNA Specificity and Autoregulation of DDX17, a Modulator of MicroRNA Biogenesis

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