RNA structure generates natural cooperativity between single-stranded RNA binding proteins targeting 5′ and 3′UTRs

AbstractTo infer the sequence and RNA structure specificities of RNA-binding proteins (RBPs) from experiments that enrich for bound sequences, we introduce a convolutional residual network which we call ResidualBind. ResidualBind significantly outperforms previous methods on experimental data from many RBP families. We interrogate ResidualBind to identify what features it has learned from high-affinity sequences with saliency analysis along with 1st-order and 2nd-orderin silicomutagenesis. We show that in addition to sequence motifs, ResidualBind learns a model that includes the number of motifs, their spacing, and both positive and negative effects of RNA structure context. Strikingly, ResidualBind learns RNA structure context, including detailed base-pairing relationships, directly from sequence data, which we confirm on synthetic data. ResidualBind is a powerful, flexible, and interpretable model that can uncovercis-recognition preferences across a broad spectrum of RBPs.

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The role of m6A modification in physiology and disease

Cell Death and Disease ◽

10.1038/s41419-020-03143-z ◽

2020 ◽

Vol 11 (11) ◽

Cited By ~ 1

Author(s):

Chuan Yang ◽

Yiyang Hu ◽

Bo Zhou ◽

Yulu Bao ◽

Zhibin Li ◽

...

Keyword(s):

Rna Structure ◽

Cellular Differentiation ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Epigenetic Modification ◽

Mrna Splicing ◽

Chemical Modifications ◽

Functional Modulation

Abstract Similar to DNA epigenetic modifications, multiple reversible chemical modifications on RNAs have been uncovered in a new layer of epigenetic modification. N6-methyladenosine (m6A), a modification that occurs in ~30% transcripts, is dynamically regulated by writer complex (methylase) and eraser (RNA demethylase) proteins, and is recognized by reader (m6A-binding) proteins. The effects of m6A modification are reflected in the functional modulation of mRNA splicing, export, localization, translation, and stability by regulating RNA structure and interactions between RNA and RNA-binding proteins. This modulation is involved in a variety of physiological behaviors, including neurodevelopment, immunoregulation, and cellular differentiation. The disruption of m6A modulations impairs gene expression and cellular function and ultimately leads to diseases such as cancer, psychiatric disorders, and metabolic disease. This review focuses on the mechanisms and functions of m6A modification in a variety of physiological behaviors and diseases.

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Sequence, Structure and Context Preferences of Human RNA Binding Proteins

10.1101/201996 ◽

2017 ◽

Cited By ~ 3

Author(s):

Daniel Dominguez ◽

Peter Freese ◽

Maria Alexis ◽

Amanda Su ◽

Myles Hochman ◽

...

Keyword(s):

Rna Structure ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Sequence Structure ◽

Rna Motifs ◽

Core Motif ◽

Contextual Features ◽

Nucleotide Context

SUMMARYProduction of functional cellular RNAs involves multiple processing and regulatory steps principally mediated by RNA binding proteins (RBPs). Here we present the affinity landscapes of 78 human RBPs using an unbiased assay that determines the sequence, structure, and context preferences of an RBP in vitro from deep sequencing of bound RNAs. Analyses of these data revealed several interesting patterns, including unexpectedly low diversity of RNA motifs, implying frequent convergent evolution of binding specificity toward a relatively small set of RNA motifs, many with low compositional complexity. Offsetting this trend, we observed extensive preferences for contextual features outside of core RNA motifs, including spaced “bipartite” motifs, biased flanking nucleotide context, and bias away from or towards RNA structure. These contextual features are likely to enable targeting of distinct subsets of transcripts by different RBPs that recognize the same core motif. Our results enable construction of “RNA maps” of RBP activity without requiring crosslinking-based assays, and provide unprecedented depth of information on the interaction of RBPs with RNA.

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RADAR: annotation and prioritization of variants in the post-transcriptional regulome of RNA-binding proteins

10.1101/474072 ◽

2018 ◽

Author(s):

Jing Zhang ◽

Jason Liu ◽

Donghoon Lee ◽

Jo-Jo Feng ◽

Lucas Lochovsky ◽

...

Keyword(s):

Transcriptional Regulation ◽

Binding Sites ◽

Rna Structure ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Network Centrality ◽

Impact Score ◽

Variant Prioritization ◽

Post Transcriptional Regulation

AbstractRNA-binding proteins (RBPs) play key roles in post-transcriptional regulation and disease. Their binding sites cover more of the genome than coding exons; nevertheless, most noncoding variant-prioritization methods only focus on transcriptional regulation. Here, we integrate the portfolio of ENCODE-RBP experiments to develop RADAR, a variant-scoring framework. RADAR uses conservation, RNA structure, network centrality, and motifs to provide an overall impact score. Then it further incorporates tissue-specific inputs to highlight disease-specific variants. Our results demonstrate RADAR can successfully pinpoint variants, both somatic and germline, associated with RBP-function dysregulation, that cannot be found by most current prioritization methods, for example variants affecting splicing.

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