Integrative analysis reveals RNA G-Quadruplexes in UTRs are selectively constrained and enriched for functional associations

Lee, David S. M.; Ghanem, Louis; Barash, Yoseph

doi:10.1101/666842

Cited by 24 publications

(29 citation statements)

References 55 publications

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“…Recent reports have demonstrated that the majority of RNA sequences that have the ability to fold into G-quadruplex structures in vitro may be generally unfolded in cells (Guo and Bartel, 2016). Still, previous reports and our data demonstrate that the G-quadruplexes must be folded in order to be efficiently bound by FMRP (Subramanian et al, 2011), and G-quadruplex sequences have been reported to be under purifying selection (Lee et al, 2019).…”

Section: Discussioncontrasting

confidence: 45%

FMRP promotes RNA localization to neuronal projections through interactions between its RGG domain and G-quadruplex RNA sequences

Goering

Hudish

Guzman

et al. 2019

Preprint

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The sorting of RNA molecules to distinct subcellular locations facilitates the activity of spatially restricted processes through local protein synthesis. This process affects thousands of transcripts yet precisely how these RNAs are trafficked to their destinations remains generally unclear. Here we have analyzed subcellular transcriptomes of FMRP-null mouse neuronal cells to identify transcripts that depend on FMRP for efficient transport to neurites. We found that these FMRP RNA localization targets contain a large enrichment of G-quadruplex sequences, particularly in their 3′ UTRs, suggesting that FMRP recognizes these sequences to promote the localization of transcripts that contain them. Fractionation of neurons derived from human Fragile X Syndrome patients revealed a high degree of conservation in the identity of FMRP localization targets between human and mouse as well as an enrichment of G-quadruplex sequences in human FMRP RNA localization targets. Using high-throughput RNA/protein interaction assays and single-molecule RNA FISH, we identified the RGG domain of FMRP as important for both interaction with G-quadruplex RNA sequences and the neuronal transport of G-quadruplex-containing transcripts. Finally, we used ribosome footprinting to identify translational regulatory targets of FMRP. The translational regulatory targets were not enriched for G-quadruplex sequences and were largely distinct from the RNA localization targets of FMRP, indicating that the two functions can be biochemically separated and are mediated through different target recognition mechanisms. These results establish a molecular mechanism underlying FMRP-mediated neuronal RNA localization and provide a framework for the elucidation of similar mechanisms governed by other RNA-binding proteins.

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Section: Discussioncontrasting

confidence: 45%

FMRP promotes RNA localization to neuronal projections through interactions between its RGG domain and G-quadruplex RNA sequences

Goering

Hudish

Guzman

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…5A and S6A) [40][41][42][43][44]. Additionally, many of the RBPs that exhibited the strongest G4-binding signal-PRPF4, GTF2F1, FAM120A, CSTF2T, and DDX6-have recently been shown to bind at putative G4 sites in mRNA UTRs [45]. However, some published G4-binding proteins such as FMR1 did not exhibit a robust signal, perhaps due to cell-type-specific variations in binding ( Fig.…”

Section: Cross-correlation Tracks Reproducibly Cluster Rbp Data Acrosmentioning

confidence: 99%

nearBynding: A flexible pipeline characterizing protein binding to local RNA structure

Busa

Favorov

Fertig

et al. 2020

Preprint

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The etiology of diseases driven by dysregulated mRNA metabolism can be elucidated by characterizing the responsible RNA-binding proteins (RBPs). Although characterizations of RBPs have been mainly focused on their binding sequences, not much has been investigated about their preferences for RNA structures. We present nearBynding, an R/Bioconductor pipeline that incorporates RBP binding sites and RNA structure information to discern structural binding preferences for an RBP. nearBynding visualizes RNA structure at and proximal to sites of RBP binding transcriptome-wide, analyzes CLIP-seq data without peak-calling, and provides a flexible scaffold to study RBP binding preferences relative to diverse RNA structure data types.

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“…Recent research revealed that the G-quadruplexes in human UTRs (Untranslated Regions) are under selective pressures [58], and some coronaviruses on bats and pangolins are closely related to SARS-CoV-2. The conservation of the potential G-quadruplexes in the SARS-CoV-2 genome under selective constraints were analyzed.…”

Section: Potential G-quadruplexes Are Under Selective Constraints In mentioning

confidence: 99%

Whole genome identification of potential G-quadruplexes and analysis of the G-quadruplex binding domain for SARS-CoV-2

Zhang

Xiao

et al. 2020

Preprint

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The Coronavirus Disease 2019 pandemic caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) quickly become a global public health emergency. Gquadruplex, one of the non-canonical secondary structures, has shown potential antiviral values. However, little is known about G-quadruplexes on the emerging SARS-CoV-2. Herein, we characterized the potential G-quadruplexes both in the positive and negative-sense viral stands. The identified potential G-quadruplexes exhibits similar features to the G-quadruplexes detected in the human transcriptome. Within some bat and pangolin related beta coronaviruses, the G-quartets rather than the loops are under heightened selective constraints. We also found that the SUD-like sequence is retained in the SARS-CoV-2 genome, while some other coronaviruses that can infect humans are depleted. Further analysis revealed that the SARS-CoV-2 SUD-like sequence is almost conserved among 16,466 SARS-CoV-2 samples. And the SARS-CoV-2 SUDcore-like dimer displayed similar electrostatic potential pattern to the SUD dimer. Considering the potential value of G-quadruplexes to serve as targets in antiviral strategy, we hope our fundamental research could provide new insights for the SARS-CoV-2 drug discovery. Respiratory Syndrome (MERS) in 2012 [2,5], and COVID-19. Scientists identified and sequenced the virus early in this outbreak, and named it SARS-CoV-2[6]. The symptoms of the patients infected with the novel coronavirus vary from person to person, and fever, cough, and fatigue are the most common ones[7-10]. The clinical chest CT (Computed tomography) and nucleic acid testing are the most typical methods of diagnosing 10]. It is worth noting that the recent achievements in AI (Artificial Intelligence) aid diagnosis technology[11] and CRISPR-Cas12-based detection methods [12] are expected to expand the diagnosis of COVID-19. Despite the great efforts of the researchers, so far, no specific clinical drugs or vaccines have been developed to cope with COVID-19. SARS-CoV-2 is a Betacoronavirus within the Coronaviridae family that is the culprit responsible for the COVID-19 pandemic [13,14] (Fig. 1A). Studies have confirmed that SARS-CoV-2 is a positive-sense single-stranded RNA ((+)ssRNA) virus with a total length of approximately 30k. The positive-sense RNA strand of SARS-CoV-2 can serve as a template to produce viral proteins related to replication, structure composition, and other functions or events [15,16]. One of the hotspots is how the SARS-CoV-2 entry the host cells. SARS-CoV-2 has shown a great affinity to the angiotensin-converting enzyme 2 (ACE2), which has been proved to be the binding receptor for SARS-CoV-2 [17,18]. After entering the host cells, the viral genomic RNA will be released to the cytoplasm, and the ORF1a/ORF1ab are subsequently translated into replicase polyproteins of pp1a/pp1ab, which will be cleaved into some non-structural proteins (nsps). These non-structure proteins ultimately form the replicase-transcriptase complex for replication and transcription....

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Integrative analysis reveals RNA G-Quadruplexes in UTRs are selectively constrained and enriched for functional associations

Cited by 24 publications

References 55 publications

FMRP promotes RNA localization to neuronal projections through interactions between its RGG domain and G-quadruplex RNA sequences

FMRP promotes RNA localization to neuronal projections through interactions between its RGG domain and G-quadruplex RNA sequences

nearBynding: A flexible pipeline characterizing protein binding to local RNA structure

Whole genome identification of potential G-quadruplexes and analysis of the G-quadruplex binding domain for SARS-CoV-2

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