A slow transcription rate causes embryonic lethality and perturbs kinetic coupling of neuronal genes

Maslon, Magdalena M.; Braunschweig, Ulrich; Aitken, Stuart; Mann, Abigail; Kilanowski, Fiona; Hunter, Chris; Blencowe, Benjamin J.; Kornblihtt, Alberto R.; Adams, Ian R.; Cáceres, Javier F.

doi:10.15252/embj.2018101244

Cited by 47 publications

(47 citation statements)

References 88 publications

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“…While we succeeded in generation of viable plants carrying a fast RNAPII mutation, we were unable to obtain plants with a mutation in a conserved residue that reduced RNAPII transcription speed in yeast. This observation is reminiscent of embryonic lethality in mice through a point mutation in the largest RNAPII subunit that decreases transcription speed . Female germline development in Arabidopsis involves more complex cellular differentiation than male germline development .…”

Section: Discussionmentioning

confidence: 99%

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Organismal benefits of transcription speed control at gene boundaries

et al. 2020

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RNA polymerase II (RNAPII) transcription is crucial for gene expression. RNAPII density peaks at gene boundaries, associating these key regions for gene expression control with limited RNAPII movement. The connections between RNAPII transcription speed and gene regulation in multicellular organisms are poorly understood. Here, we directly modulate RNAPII transcription speed by point mutations in the second largest subunit of RNAPII in Arabidopsis thaliana. A RNAPII mutation predicted to decelerate transcription is inviable, while accelerating RNAPII transcription confers phenotypes resembling auto‐immunity. Nascent transcription profiling revealed that RNAPII complexes with accelerated transcription clear stalling sites at both gene ends, resulting in read‐through transcription. The accelerated transcription mutant NRPB2‐Y732F exhibits increased association with 5′ splice site (5′SS) intermediates and enhanced splicing efficiency. Our findings highlight potential advantages of RNAPII stalling through local reduction in transcription speed to optimize gene expression for the development of multicellular organisms.

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Section: Discussionmentioning

confidence: 99%

“…ª 2020 The Authors EMBO reports 21: e49315 | 2020 decreases transcription speed [43]. Female germline development in Arabidopsis involves more complex cellular differentiation than male germline development [44].…”

Section: Rnapii Transcription Speed and Organismal Developmentmentioning

confidence: 99%

Organismal benefits of transcription speed control at gene boundaries

et al. 2020

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“…Transcription through gene bodies is subject to dynamic changes in elongation rate, and is a highly regulated process in development and differentiation ( Chen et al., 2018 ; Jonkers and Lis, 2015 ; Bai et al., 2010 ; Maslon et al., 2019 ; Tan et al., 2016 ; White et al., 2011 ). We propose PRL3-DDX21 regulation of productive transcription elongation functions as a fine-tuning mechanism for matching the regenerative response with tissue needs and an opportunity for specifically targeting cancer cells in a non-regenerative setting.…”

Section: Discussionmentioning

confidence: 99%

PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation

Johansson

Marie

et al. 2020

Developmental Cell

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Summary Melanocytes, replenished throughout life by melanocyte stem cells (MSCs), play a critical role in pigmentation and melanoma. Here, we reveal a function for the metastasis-associated phosphatase of regenerating liver 3 (PRL3) in MSC regeneration. We show that PRL3 binds to the RNA helicase DDX21, thereby restricting productive transcription by RNAPII at master transcription factor (MITF)-regulated endolysosomal vesicle genes. In zebrafish, this mechanism controls premature melanoblast expansion and differentiation from MSCs. In melanoma patients, restricted transcription of this endolysosomal vesicle pathway is a hallmark of PRL3-high melanomas. Our work presents the conceptual advance that PRL3-mediated control of transcriptional elongation is a differentiation checkpoint mechanism for activated MSCs and has clinical relevance for the activity of PRL3 in regenerating tissue and cancer.

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“…Whether RP-Prp8 mutations alter ubiquitin binding remains to be determined. Finally, a growing body of evidence suggests reciprocal coupling of RNA processing and transcription, as splicing factors have been implicated in the regulation of transcription initiation, elongation rate of Pol II and the choice of transcriptional start sites (Fiszbein et al, 2019;Lin et al, 2008;Maslon et al, 2019). Splicing factor malfunction can thus manifest in a noticeable shift in gene expression profile rather than obvious splicing defects.…”

Section: Research Articlementioning

confidence: 99%

A Drosophila model to study retinitis pigmentosa pathology associated with mutations in the core splicing factor Prp8

Stanković

Claudius

Schertel

et al. 2020

Disease Models &Amp; Mechanisms

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Retinitis pigmentosa (RP) represents genetically heterogeneous and clinically variable disease characterized by progressive degeneration of photoreceptors resulting in a gradual loss of vision. The autosomal dominant RP type 13 (RP13) has been linked to the malfunction of PRPF8, an essential component of the spliceosome. Over 20 different RP-associated PRPF8 mutations have been identified in human patients. However, the cellular and molecular consequences of their expression in vivo in specific tissue contexts remain largely unknown. Here, we establish a Drosophila melanogaster model for RP13 by introducing the nine distinct RP mutations into the fly PRPF8 ortholog prp8 and express the mutant proteins in precise spatiotemporal patterns using the Gal4/UAS system. We show that all nine RP-Prp8 mutant proteins negatively impact developmental timing, albeit to a different extent, when expressed in the endocrine cells producing the primary insect moulting hormone. In the developing eye primordium, uncommitted epithelial precursors rather than differentiated photoreceptors appeared sensitive to Prp8 malfunction. Expression of the two most pathogenic variants, Prp8 S>F and Prp8 H>R , induced apoptosis causing alterations to the adult eye morphology. The affected tissue mounted stress and cytoprotective responses, while genetic programs underlying neuronal function were attenuated. Importantly, the penetrance and expressivity increased under prp8 heterozygosity. In contrast, blocking apoptosis alleviated cell loss but not the redox imbalance. Remarkably, the pathogenicity of the RP-Prp8 mutations in Drosophila correlates with the severity of clinical phenotypes in patients carrying the equivalent mutations, highlighting the suitability of the Drosophila model for in-depth functional studies of the mechanisms underlying RP13 etiology. This article has an associated First Person interview with the first author of the paper.

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A slow transcription rate causes embryonic lethality and perturbs kinetic coupling of neuronal genes

Cited by 47 publications

References 88 publications

Organismal benefits of transcription speed control at gene boundaries

Organismal benefits of transcription speed control at gene boundaries

PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation

A Drosophila model to study retinitis pigmentosa pathology associated with mutations in the core splicing factor Prp8

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