Native G-quadruplexes Stabilization Impairs Transcription Initiation
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ABSTRACT:
PROVIDER: PRJNA739982 | ENA |
REPOSITORIES: ENA
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Project description:G-quadruplexes (G4s) are noncanonical DNA secondary structures formed through the self-association of guanines. They are distributed genome-widely and participate in multiple biological processes including gene transcription, and quadruplex-targeted ligands serve as potential therapeutic agents for DNA-targeted therapies. However, the roles of G-quadruplexes in transcriptional regulation remains elusive. Here, we establish a sensitive G4-CUT&Tag method for genome-wide profiling of native G-quadruplexes with high resolution and specificity. We find that native G-quadruplex signals are cell-type specific and are associated with transcriptional regulatory elements with active epigenetic modifications. Promoter-proximal RNA polymerase II pausing promotes native G-quadruplex formation, oppositely, G-quadruplex stabilization by quadruplex-targeted ligands globally reduces RNA polymerase II occupancy at gene promoters as well as nascent RNA synthesis. Moreover, G-quadruplex stabilization modulates chromatin states and impedes transcription initiation via inhibiting the loading of general transcription factors to promoters.Together, these studies reveal a reciprocal regulation between native G-quadruplex dynamics and gene transcription in the genome, which will deepen our knowledge of G-quadruplex biology towards considering therapeutically targeting G-quadruplexes in human diseases.
2021-07-19 | GSE178668 | GEO
Project description:In eukaryotic translation, the termination and recycling phases are linked to subsequent initiation by persistence of several factors. These comprise the large eIF3 complex, eIF3j (Hcr1 in yeast) and the ATP-binding cassette protein ABCE1 (Rli1 in yeast). The ATPase is mainly active as a recycling factor, but it can remain bound to the dissociated 40S subunit until formation of 43S pre-initiation complexes. However, its functional role and native architectural context remains largely enigmatic. Here, we present an architectural inventory of native yeast and human ABCE1-containing pre-initiation complexes by cryo-EM. We found that ABCE1 was mostly associated with early 43S but also later 48S phases of initiation. It adopted a novel hybrid conformation of its nucleotide binding sites, which was stabilized by the N-terminus of eIF3j. Further, eIF3j occupied the mRNA entry channel via its ultimate C-terminus explaining its antagonistic role with respect to mRNA binding. Moreover, the native human samples provided a near-complete molecular picture of the architecture and sophisticated interaction network of the 43S-bound eIF3 complex and also the eIF2 ternary complex containing the initiator tRNA.
2020-10-16 | PXD020849 | Pride
Project description:In vitro, some RNAs can form stable four-stranded structures known as G-quadruplexes. Although RNA G-quadruplex structures have been implicated in post-transcriptional gene regulation and diseases, direct evidence for quadruplex formation in cells has been lacking. Here, we developed a suite of methods that identify RNAs with quadruplex-forming ability and measure their folding state in living cells. Applying these methods to mammalian cell lines, the budding yeast S. cerevisiae and several bacteria, we characterized the folding landscapes of RNA G-quadruplexes in these species.
2016-09-24 | GSE83617 | GEO
Project description:Translational control is a key determinant of protein abundance, which in turns defines the physiology and pathology of human cells. Initiation of translation is highly regulated in eukaryotes and is considered as the rate-limiting step of protein synthesis. mRNA secondary structures in 5’ untranslated region (UTR) and associated helicases have been characterised as key determinants of translation initiation. Nevertheless the transcriptome-wide contribution of non-canonical secondary structures, such as RNA G-quadruplexes (rG4s), to the translation of human mRNAs remains largely unappreciated. Here we use a ribosome profiling strategy to investigate the translational landscape associated to rG4s-containing mRNAs and the contribution of two rG4s-specialised DExH-box helicases, DHX9 and DHX36, to translation initiation in human cells. We show that rG4-forming sequences in 5’-UTR is associated with decreased translation efficiency which correlate with an increased ribosome density within the 5’-UTRs. We found that rG4s contribute to the translation of upstream open reading frames, and as a consequence, thwart the translation of the associated protein coding sequences (CDS). Depletion of the DHX36 and DHX9 helicases demonstrated that the formation of the rG4 structural motif rather than its nucleotide sequence mediate translation initiation. Our findings unveil a role for non-canonical structures in defining alternative 5’ starts for human mRNAs translation initiation.
2018-04-30 | GSE105082 | GEO
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Project description:Global analyses of RNA G-quadruplexes
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Project description:The identification of DNA G-quadruplexes (G4s) in the genome is important to study different biological processes in which these structures play a role, such as genome rearrangement, transcriptional regulation and DNA replication. G4-seq allowed the high-throughput experimental mapping of G-quadruplexes in the human genome. We developed here an improved version of this method, named G4-seq2, which we applied to generate G-quadruplexes genomic maps for 12 species, selected as important models organism to study development or as pathogens of clinical relevance. Those multi-species maps, publicly available for the community, will allow to further understand the design principle of G-quadruplex formation in genomic context, to study G-quadruplex biology in those model organisms, to predict ligand targeting for therapeutic usage and to design G-quadruplex computational predictors based on genome-wide experimental measurements.
2018-08-01 | GSE110582 | GEO
Project description:Comparison of gene expresion profile of 4 SC clones and 4 SI clones at different time points defined a stabilization competency signiture required for successful reprogramming mRNA profilling 4 SI clones at 5 time points, 4 SC clones at 6 time points, and 3 feeder samples.
2013-01-01 | E-GEOD-42100 | biostudies-arrayexpress
Project description:RNA secondary structures have been increasingly reported to serve critical regulatory roles in post-transcriptional gene regulation. RNA G-quadruplex secondary structures can serve as cis-elements to recruit splicing factors and regulate alternative RNA splicing. We recently showed that RNA G-quadruplexes play a critical regulatory role in regulating alternative splicing during the epithelial mesenchymal transition. Due to the critical role alternative splicing plays in human health and disease, an unmet need exists to identify small molecule modulators of alternative splicing. In this study, we performed high-throughput screening using a dual-output splicing reporter to identify small molecules capable of regulating alternative splicing by interacting with RNA secondary structure G-quadruplexes. We identify emetine and its analog cephaeline as small molecules that denature RNA G-quadruplexes in a sequence and location independent manner to modify alternative splicing. Transcriptome analysis reveals that treatment with emetine globally regulates alternative splicing, including events associated with exon-proximal G-quadruplexes. These data suggest a critical role for emetine and cephealine as splicing regulators with the selective ability to disrupt RNA G-quadruplex-associated alternative splicing in vivo.
2019-02-01 | GSE113505 | GEO
Project description:We report the RNA-seq data for rat nucleus pulposus cells after stabilizing G-Quadruplexes (G4). We sequenced rat nucleus pulposus cells treated with PDS, Braco-19 and Phen-DC3 separately and untreated with these G4 stabilizers, which could stabilize G4 structure in cells.
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