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

Zhang, Jing; Liu, Jason; Lee, Dong‐Hoon; Feng, Jo-Jo; Lochovsky, Lucas; Lou, Shaoke; Rutenberg-Schoenberg, Michael; Gerstein, Mark

doi:10.1186/s13059-020-01979-4

Cited by 10 publications

(13 citation statements)

References 53 publications

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“…Lines of previous studies have demonstrated that truly functional CREs are highly conserved across both populations and species when compared to random genomic regions, as reflected by their depleted patterns in common variants and higher conservation scores in comparative genomics analysis ( 33 , 34 ). Therefore, we further compared the DIRECT-NET’s predicted HC CREs with the MC and LC regions using both cross-population and cross-species conservation.…”

Section: Resultsmentioning

confidence: 86%

DIRECT-NET: An efficient method to discover cis-regulatory elements and construct regulatory networks from single-cell multiomics data

Zhang

Nie

2022

Sci. Adv.

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The emergence of single-cell multiomics data provides unprecedented opportunities to scrutinize the transcriptional regulatory mechanisms controlling cell identity. However, how to use those datasets to dissect the cis-regulatory element (CRE)–to–gene relationships at a single-cell level remains a major challenge. Here, we present DIRECT-NET, a machine-learning method based on gradient boosting, to identify genome-wide CREs and their relationship to target genes, either from parallel single-cell gene expression and chromatin accessibility data or from single-cell chromatin accessibility data alone. By extensively evaluating and characterizing DIRECT-NET’s predicted CREs using independent functional genomics data, we find that DIRECT-NET substantially improves the accuracy of inferring CRE-to-gene relationships in comparison to existing methods. DIRECT-NET is also capable of revealing cell subpopulation–specific and dynamic regulatory linkages. Overall, DIRECT-NET provides an efficient tool for predicting transcriptional regulation codes from single-cell multiomics data.

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Section: Resultsmentioning

confidence: 86%

DIRECT-NET: An efficient method to discover cis-regulatory elements and construct regulatory networks from single-cell multiomics data

Zhang

Nie

2022

Sci. Adv.

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“…To determine the effect of these 3′-UTR piSNVs on RBP binding, we integrated RBP motif and CLIP-seq-derived RBP binding data 38 , 39 for all identified 3’-UTR piSNVs, which revealed 24 significantly enriched RBPs. Abnormal expression of RBPs leads to tumorigenesis 3 , so we detected the differentially expressed RBPs between tumor and corresponding normal tissues in different cancer types (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…PIVAR algorithm was our previously developed to evaluate the impact of mutations on posttranscriptional regulation 6 . We updated PIVAR algorithm to evaluate the impact of mutations on posttranscriptional regulation by adding the latest 318 eCLIP-seq data from ENCODE (112 RBPs) to identify 3′-UTR piSNVs 38 , 39 , which could disrupt the binding between RNAs and RBPs. We used the Wilcoxon rank-sum test to compare the distribution of the 3′-UTR piSNV ratio (ratio of 3′-UTR piSNVs to 3′-UTR SNVs) between the control samples and samples of each cancer type.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, we downloaded 247 positional weight matrices (PWMs) of the inferred RNA binding motif from the AURA database 82 , which were used to call motif matches in the transcriptome. RBP motif and CLIP-seq-derived RBP binding were integrated to identify 3′-UTR piSNVs 38 , 39 ; FDR and OR values were calculated with Fisher’s exact tests to identify the significantly enriched RBPs affected by 3′-UTR piSNVs (FDR < 0.05 and OR > 1).…”

Section: Methodsmentioning

confidence: 99%

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Comprehensive characterization of posttranscriptional impairment-related 3′-UTR mutations in 2413 whole genomes of cancer patients

Wei

Gao

et al. 2022

npj Genom. Med.

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The 3′ untranslated region (3′-UTR) is the vital element regulating gene expression, but most studies have focused on variations in RNA-binding proteins (RBPs), miRNAs, alternative polyadenylation (APA) and RNA modifications. To explore the posttranscriptional function of 3′-UTR somatic mutations in tumorigenesis, we collected whole-genome data from 2413 patients across 18 cancer types. Our updated algorithm, PIVar, revealed 25,216 3′-UTR posttranscriptional impairment-related SNVs (3′-UTR piSNVs) spanning 2930 genes; 24 related RBPs were significantly enriched. The somatic 3′-UTR piSNV ratio was markedly increased across all 18 cancer types, which was associated with worse survival for four cancer types. Several cancer-related genes appeared to facilitate tumorigenesis at the protein and posttranscriptional regulation levels, whereas some 3′-UTR piSNV-affected genes functioned mainly via posttranscriptional mechanisms. Moreover, we assessed immune cell and checkpoint characteristics between the high/low 3′-UTR piSNV ratio groups and predicted 80 compounds associated with the 3′-UTR piSNV-affected gene expression signature. In summary, our study revealed the prevalence and clinical relevance of 3′-UTR piSNVs in cancers, and also demonstrates that in addition to affecting miRNAs, 3′-UTR piSNVs perturb RBPs binding, APA and m6A RNA modification, which emphasized the importance of considering 3′-UTR piSNVs in cancer biology.

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“…Large-scale identification and analysis of RBP targets will also aid in understanding the role of RBPs in disease. Recent advances in technology have made this possible [ 296 ]; however, these studies would be well complemented by follow up studies in tissues of interest.…”

Section: Discussionmentioning

confidence: 99%

Emerging Roles of RNA-Binding Proteins in Neurodevelopment

Parra

Johnston

2022

JDB

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Diverse cell types in the central nervous system (CNS) are generated by a relatively small pool of neural stem cells during early development. Spatial and temporal regulation of stem cell behavior relies on precise coordination of gene expression. Well-studied mechanisms include hormone signaling, transcription factor activity, and chromatin remodeling processes. Much less is known about downstream RNA-dependent mechanisms including posttranscriptional regulation, nuclear export, alternative splicing, and transcript stability. These important functions are carried out by RNA-binding proteins (RBPs). Recent work has begun to explore how RBPs contribute to stem cell function and homeostasis, including their role in metabolism, transport, epigenetic regulation, and turnover of target transcripts. Additional layers of complexity are provided by the different target recognition mechanisms of each RBP as well as the posttranslational modifications of the RBPs themselves that alter function. Altogether, these functions allow RBPs to influence various aspects of RNA metabolism to regulate numerous cellular processes. Here we compile advances in RNA biology that have added to our still limited understanding of the role of RBPs in neurodevelopment.

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

Cited by 10 publications

References 53 publications

DIRECT-NET: An efficient method to discover cis-regulatory elements and construct regulatory networks from single-cell multiomics data

DIRECT-NET: An efficient method to discover cis-regulatory elements and construct regulatory networks from single-cell multiomics data

Comprehensive characterization of posttranscriptional impairment-related 3′-UTR mutations in 2413 whole genomes of cancer patients

Emerging Roles of RNA-Binding Proteins in Neurodevelopment

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