Virus-Induced Changes in mRNA Secondary Structure Uncover cis-Regulatory Elements that Directly Control Gene Expression

Mizrahi, Orel; Nachshon, Aharon; Shitrit, Alina; Gelbart, Idit Anna; Dobešová, Martina; Brenner, Shirley; Kahana, Chaim; Stern-Ginossar, Noam

doi:10.1016/j.molcel.2018.09.003

Cited by 43 publications

(37 citation statements)

References 63 publications

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“…Recent studies have also revealed that mRNAs can undergo structural rearrangements throughout an mRNA's life. For example, when zebrafish embryos undergo the maternal-to-zygotic transition (Beaudoin et al, 2018), or as mRNAs transition from the nucleus to the cytoplasm (Adivarahan et al, 2018;Sun et al, 2019), or upon translation of mRNAs by ribosomes (Beaudoin et al, 2018;Mizrahi et al, 2018;Mustoe et al, 2018). While these studies demonstrate that mRNAs can adopt distinct structural conformations, they provide limited insights into the dynamics of mRNA structure, especially on the short timescales at which AGO-target interactions likely occur.…”

Section: Introductionmentioning

confidence: 99%

mRNA structural dynamics shape Argonaute-target interactions

Ruijtenberg

Sonneveld

Cui

et al. 2019

Preprint

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Small RNAs (such as miRNAs, siRNAs and piRNAs) regulate protein expression in a wide variety of biological processes and play an important role in cellular function, development and disease. Association of small RNAs with Argonaute (AGO) family proteins guide AGO to target RNAs, generally resulting in target silencing through transcriptional silencing, translational repression or mRNA degradation. Here we develop a live-cell single-molecule imaging assay to simultaneously visualize translation of individual mRNA molecules and their silencing by human AGO2-siRNA complexes. We find that siRNA target sites are commonly masked in vivo by RNA secondary structures, which inhibit AGO2-target interactions.Translating ribosomes unmask AGO2 binding sites, stimulating AGO2-target interactions and promoting mRNA degradation. Using a combination of mathematical modeling and experiments, we find that mRNA structures are highly heterogeneous and continuously refolding. We show that structural dynamics of mRNAs shape AGO2-target recognition, which may be a common feature controlling mRNA-protein interactions.

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Section: Introductionmentioning

confidence: 99%

mRNA structural dynamics shape Argonaute-target interactions

Ruijtenberg

Sonneveld

Cui

et al. 2019

Preprint

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“…Secondary structures which serve as cis‐elements may be dynamically altered during immune responses. Recently, a global profiling study of mRNA secondary structures found that viral infection leads to a change in the secondary structures of 3′ UTR of cellular mRNAs . These structurally dynamic regions are enriched in RBP binding sites and regulate RBP‐mediated mRNA stabilisation upon viral infection.…”

Section: Inflammation‐related Mrnas Are Regulated By a Set Of Rna Binmentioning

confidence: 99%

“…Recently, a global profiling study of mRNA secondary structures found that viral infection leads to a change in the secondary structures of 3 0 UTR of cellular mRNAs. 13 These structurally dynamic regions are enriched in RBP binding sites and regulate RBP-mediated mRNA stabilisation upon viral infection. Thus, ciselements may be dynamically generated or abolished during immune responses, allowing for the intricate regulation of immune-related transcripts in a manner dependent on stimulation.…”

Section: Cis-elements In the 3 0 Utr Of Inflammatory Mrnasmentioning

confidence: 99%

Post‐transcriptional control of immune responses and its potential application

Yoshinaga

Takeuchi

2019

Clin & Trans Imm

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Inflammation is the host response against stresses such as infection. Although the inflammation process is required for the elimination of pathogens, uncontrolled inflammation leads to tissue destruction and inflammatory diseases. To avoid this, the inflammatory response is tightly controlled by multiple layers of regulation. Post‐transcriptional control of inflammatory mRNAs is increasingly understood to perform critical roles in this process. This is mediated primarily by a set of RNA binding proteins (RBPs) including tristetraprolin, Roquin and Regnase‐1, and RNA methylases. These key regulators coordinate the inflammatory response by modulating mRNA pools in both immune and local nonimmune cells. In this review, we provide an overview of the post‐transcriptional coordination of immune responses in various tissues and discuss how RBP‐mediated regulation of inflammation may be harnessed as a potential class of treatments for inflammatory diseases.

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“…However, RNA structures derived from in vivo probing do not necessarily resemble those from in vitro and in silico studies . The helicase activity of ribosomes causes transient alterations in the structure, and a multitude of RNA‐binding proteins (RBPs) may stabilize structures that would not be preferred in a setting with minimalized components . Conversely, some thermostable structures have been found to exist largely in denatured states within cells .…”

Section: Vrna Interactions With Host Proteins May Confound Models Dermentioning

confidence: 99%

“…Conversely, some thermostable structures have been found to exist largely in denatured states within cells . To complicate matters further, in vivo structures of cellular RNAs have been shown to vary over time, following virus infection . The potential for in‐depth analysis of in vivo vRNA structure is seen in the work of Li et al, examining Zika vRNA with two different probing methods.…”

Section: Vrna Interactions With Host Proteins May Confound Models Dermentioning

confidence: 99%

Flavors of Flaviviral RNA Structure: towards an Integrated View of RNA Function from Translation through Encapsidation

et al. 2019

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For many viruses, RNA is the holder of genetic information and serves as the template for both replication and translation. While host and viral proteins play important roles in viral decision‐making, the extent to which viral RNA (vRNA) actively participates in translation and replication might be surprising. Here, the focus is on flaviviruses, which include common human scourges such as dengue, West Nile, and Zika viruses, from an RNA‐centric viewpoint. In reviewing more recent findings, an attempt is made to fill knowledge gaps and revisit some canonical views of vRNA structures involved in replication. In particular, alternative views are offered on the nature of the flaviviral promoter and genome cyclization, and the feasibility of refining in vitro‐derived models with modern RNA probing and sequencing methods is pointed out. By tracing vRNA structures from translation through encapsidation, a dynamic molecule closely involved in the self‐regulation of viral replication is revealed.

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Virus-Induced Changes in mRNA Secondary Structure Uncover cis-Regulatory Elements that Directly Control Gene Expression

Cited by 43 publications

References 63 publications

mRNA structural dynamics shape Argonaute-target interactions

mRNA structural dynamics shape Argonaute-target interactions

Post‐transcriptional control of immune responses and its potential application

Flavors of Flaviviral RNA Structure: towards an Integrated View of RNA Function from Translation through Encapsidation

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