Pervasive Chromatin-RNA Binding Protein Interactions Enable RNA-Based Regulation of Transcription

Xiao, Rui; Chen, Jia Yu; Liang, Zhengyu; Luo, Daji; Chen, Geng; Lu, Zhi John; Yang, Chen; Zhou, Bing; Li, Hairi; Du, Xian; Yang, Yang; San, Mingkui; Wei, Xintao; Li, Wen; Lécuyer, Éric; Graveley, Brenton R.; Yeo, G; Burge, Christopher B.; Zhang, Michael Q.; Zhou, Yu; Fu, Xiang Dong

doi:10.1016/j.cell.2019.06.001

Cited by 241 publications

(218 citation statements)

References 76 publications

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“…Although a direct comparison of the relative impact of transcription and splicing dysregulation in brain tumors has not been performed yet, it is likely that the two pathways cooperate. Indeed, splicing is mechanistically coupled to transcription and, in turn, splicing factors elicit widespread effects on transcription [144]. This tight connection between the transcription and processing of nascent RNAs needs to be precisely controlled in order to avoid detrimental effects originating from the expression of aberrant gene products.…”

Section: Resultsmentioning

confidence: 99%

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Bielli

Pagliarini

Pieraccioli

et al. 2019

Cells

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Brain tumors are a heterogeneous group of neoplasms ranging from almost benign to highly aggressive phenotypes. The malignancy of these tumors mostly relies on gene expression reprogramming, which is frequently accompanied by the aberrant regulation of RNA processing mechanisms. In brain tumors, defects in alternative splicing result either from the dysregulation of expression and activity of splicing factors, or from mutations in the genes encoding splicing machinery components. Aberrant splicing regulation can generate dysfunctional proteins that lead to modification of fundamental physiological cellular processes, thus contributing to the development or progression of brain tumors. Herein, we summarize the current knowledge on splicing abnormalities in brain tumors and how these alterations contribute to the disease by sustaining proliferative signaling, escaping growth suppressors, or establishing a tumor microenvironment that fosters angiogenesis and intercellular communications. Lastly, we review recent efforts aimed at developing novel splicing-targeted cancer therapies, which employ oligonucleotide-based approaches or chemical modulators of alternative splicing that elicit an impact on brain tumor biology.

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Section: Resultsmentioning

confidence: 99%

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Bielli

Pagliarini

Pieraccioli

et al. 2019

Cells

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“…5). Silencing community members TARDBP and RBM22 are RNA-dependent regulators of transcription 46 but have not yet been directly implicated in X chromosome silencing. The significant interactivity of the binding sites of the 5′ Silencing community members suggests formation of a specific coordinated RNP on XIST.…”

Section: Communities Of Xist-binding Proteinsmentioning

confidence: 99%

RNP-MaP: In-cell analysis of protein interaction networks defines functional hubs in RNA

Weidmann¹,

Mustoe²,

Jariwala³

et al. 2020

Preprint

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RNAs interact with networks of proteins to form complexes (RNPs) that govern many biological processes, but these networks are currently impossible to examine in a comprehensive way.We developed a live-cell chemical probing strategy for mapping protein interaction networks in any RNA with single-nucleotide resolution. This RNP-MaP strategy (RNP network analysis by mutational profiling) simultaneously detects binding by and cooperative interactions involving multiple proteins with single RNA molecules. RNP-MaP revealed that two structurally related, but sequence-divergent noncoding RNAs, RNase P and RMRP, share nearly identical RNP networks and, further, that protein interaction network hubs identify function-critical sites in these RNAs. RNP-MaP identified numerous protein interaction networks within the XIST long noncoding RNA that are conserved between mouse and human RNAs and distinguished communities of proteins that network together on XIST. RNP-MaP data show that the Xist E region is densely networked by protein interactions and that PTBP1, MATR3, and TIA1 proteins each interface with the XIST E region via two distinct interaction modes; and we find that the XIST E region is sufficient to mediate RNA foci formation in cells. RNP-MaP will enable discovery and mechanistic analysis of protein interaction networks across any RNA in cells. RESULTS RNP-MaP ValidationTo comprehensively map protein interaction networks of an RNA of interest, we identified a cellpermeable reagent, NHS-diazirine (SDA), that can rapidly label RNA nucleotides at sites of protein binding. SDA has two reactive moieties: a succinimidyl ester and a diazirine ( Fig. 1a).Succinimidyl esters react to form amide bonds with amines such as those found in lysine side chains. When photoactivated with long-wavelength ultraviolet light (UV-A, 365 nm), diazirines form carbene or diazo intermediates 10 , which are broadly reactive to nucleotide sugar and base moieties. The two-step reaction of SDA thus crosslinks protein lysine residues with RNA with a distance governed by SDA linker length (4 Å) and lysine flexibility (6 Å). Lysine is one of the most prevalent amino acids in RNA-binding domains 11 , and photo-intermediate lifetimes are short; thus, SDA is expected to crosslink short-range RNA-protein interactions relatively independently of local RNA structure or protein properties. To perform crosslinking, live cells are treated with SDA for a short time and then exposed to UV-A light.To detect SDA-mediated RNA-protein crosslinks, we use the MaP reverse transcription technology ( Fig. 1b). SDA-treated cells are lysed and crosslinked proteins are digested to short peptide adducts. Adduct-containing RNA is then used as a template for relaxed-fidelity reverse transcription 12,13 . Under MaP conditions, reverse transcriptase reads through adduct-containing nucleotides and incorporates non-templated nucleotides into the product DNA at the site of RNAprotein crosslinks. Importantly, because transcription reads through adducts, RNP-MaP detects multiple pro...

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“…The tug of war between activation and repression mechanisms quantitatively regulates FLC expression. Kuninger et al, 2002;Ji et al, 2013;Xiao et al, 2019). For example, the mammalian splicing regulator SR protein SRSF2 regulates transcriptional elongation by controlling Pol II pause release at the 59 end of a gene (Ji et al, 2013).…”

Section: Tug Of War At Flc Chromatinmentioning

confidence: 99%

Autonomous Pathway: FLOWERING LOCUS C Repression through an Antisense-Mediated Chromatin-Silencing Mechanism

Fang

Zhu

et al. 2019

Plant Physiol.

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The timing of flowering is vital for plant reproductive success and is therefore tightly regulated by endogenous and exogenous cues. In summer annual Arabidopsis (Arabidopsis thaliana) accessions, like Columbia-0, rapid flowering is promoted by repression of the floral repressor FLOWERING LOCUS C (FLC). This is through the activity of the autonomous pathway, a group of proteins with diverse functions including RNA 39-end processing factors, spliceosome components, a transcription elongation factor, and chromatin modifiers. These factors function at the FLC locus linking alternative processing of an antisense long noncoding RNA, called COOLAIR, with delivery of a repressive chromatin environment that affects the transcriptional output. The transcriptional output feeds back to influence the chromatin environment, reinforcing and stabilizing that state. This review summarizes our current knowledge of the autonomous pathway and compares it with similar cotranscriptional mechanisms in other organisms.

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Pervasive Chromatin-RNA Binding Protein Interactions Enable RNA-Based Regulation of Transcription

Cited by 241 publications

References 76 publications

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

RNP-MaP: In-cell analysis of protein interaction networks defines functional hubs in RNA

Autonomous Pathway: FLOWERING LOCUS C Repression through an Antisense-Mediated Chromatin-Silencing Mechanism

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