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Global analysis of RNA-binding proteins identifies a positive feedback loop between LARP1 and MYC that promotes tumorigenesis.

Cellular and molecular life sciences : CMLS · 2022 · 79(3): 147

In addition to genomic alterations, aberrant changes in post-transcriptional regulation can modify gene function and drive cancer development. RNA-binding proteins (RBPs) are a large class of post-transcriptional regulators that have been increasingly implicated in carcinogenesis. By integrating multi-omics data, we …

PMID 35195778 DOI ↗

Pseudouridine synthases modify human pre-mRNA co-transcriptionally and affect pre-mRNA processing.

Molecular cell · 2022 · 82(3): 645-659.e9

Pseudouridine is a modified nucleotide that is prevalent in human mRNAs and is dynamically regulated. Here, we investigate when in their life cycle mRNAs become pseudouridylated to illuminate the potential regulatory functions of endogenous mRNA pseudouridylation. Using single-nucleotide resolution pseudouridine …

PMID 35051350 DOI ↗

Inhibition of YTHDF2 triggers proteotoxic cell death in MYC-driven breast cancer.

Molecular cell · 2021 · 81(15): 3048-3064.e9

RNA-binding proteins (RBPs) are critical regulators of post-transcriptional gene expression, and aberrant RBP-RNA interactions can promote cancer progression. Here, we interrogate the function of RBPs in cancer using pooled CRISPR-Cas9 screening and identify 57 RBP candidates with distinct roles in …

PMID 34216543 DOI ↗

Robust single-cell discovery of RNA targets of RNA-binding proteins and ribosomes.

Nature methods · 2021 · 18(5): 507-519

RNA-binding proteins (RBPs) are critical regulators of gene expression and RNA processing that are required for gene function. Yet the dynamics of RBP regulation in single cells is unknown. To address this gap in understanding, we developed STAMP (Surveying Targets …

PMID 33963355 DOI ↗

S-nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD.

Proceedings of the National Academy of Sciences of the United States of America · 2021 · 118(11)

Rare genetic mutations result in aggregation and spreading of cognate proteins in neurodegenerative disorders; however, in the absence of mutation (i.e., in the vast majority of "sporadic" cases), mechanisms for protein misfolding/aggregation remain largely unknown. Here, we show environmentally induced …

PMID 33692125 DOI ↗

A CRISPR RNA-binding protein screen reveals regulators of RUNX1 isoform generation.

Blood advances · 2021 · 5(5): 1310-1323

The proper balance of hematopoietic stem cell (HSC) self-renewal and differentiation is critical for normal hematopoiesis and is disrupted in hematologic malignancy. Among regulators of HSC fate, transcription factors have a well-defined central role, and mutations promote malignant transformation. More …

PMID 33656539 DOI ↗

Author Correction: A large-scale binding and functional map of human RNA-binding proteins.

Nature · 2021 · 589(7842): E5

PMID 33402748 DOI ↗

Transcriptome-wide profiles of circular RNA and RNA-binding protein interactions reveal effects on circular RNA biogenesis and cancer pathway expression.

Genome medicine · 2020 · 12(1): 112

Circular RNAs (circRNAs) are stable, often highly expressed RNA transcripts with potential to modulate other regulatory RNAs. A few circRNAs have been shown to bind RNA-binding proteins (RBPs); however, little is known about the prevalence and distribution of these interactions …

PMID 33287884 DOI ↗

Footprinting SHAPE-eCLIP Reveals Transcriptome-wide Hydrogen Bonds at RNA-Protein Interfaces.

Molecular cell · 2020 · 80(5): 903-914.e8

Discovering the interaction mechanism and location of RNA-binding proteins (RBPs) on RNA is critical for understanding gene expression regulation. Here, we apply selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) on in vivo transcripts compared to protein-absent transcripts in four …

PMID 33242392 DOI ↗

Zmat3 Is a Key Splicing Regulator in the p53 Tumor Suppression Program.

Molecular cell · 2020 · 80(3): 452-469.e9

Although TP53 is the most commonly mutated gene in human cancers, the p53-dependent transcriptional programs mediating tumor suppression remain incompletely understood. Here, to uncover critical components downstream of p53 in tumor suppression, we perform unbiased RNAi and CRISPR-Cas9-based genetic screens …

PMID 33157015 DOI ↗

DDX5 promotes oncogene C3 and FABP1 expressions and drives intestinal inflammation and tumorigenesis.

Life science alliance · 2020 · 3(10)

Tumorigenesis in different segments of the intestinal tract involves tissue-specific oncogenic drivers. In the colon, complement component 3 (C3) activation is a major contributor to inflammation and malignancies. By contrast, tumorigenesis in the small intestine involves fatty acid-binding protein 1 …

PMID 32817263 DOI ↗

Large-scale tethered function assays identify factors that regulate mRNA stability and translation.

Nature structural & molecular biology · 2020 · 27(10): 989-1000

The molecular functions of the majority of RNA-binding proteins (RBPs) remain unclear, highlighting a major bottleneck to a full understanding of gene expression regulation. Here, we develop a plasmid resource of 690 human RBPs that we subject to luciferase-based 3'-untranslated-region …

PMID 32807991 DOI ↗

A role for alternative splicing in circadian control of exocytosis and glucose homeostasis.

Genes & development · 2020 · 34(15-16): 1089-1105

The circadian clock is encoded by a negative transcriptional feedback loop that coordinates physiology and behavior through molecular programs that remain incompletely understood. Here, we reveal rhythmic genome-wide alternative splicing (AS) of pre-mRNAs encoding regulators of peptidergic secretion within pancreatic …

PMID 32616519 DOI ↗

Expanded encyclopaedias of DNA elements in the human and mouse genomes.

Nature · 2020 · 583(7818): 699-710

The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded …

PMID 32728249 DOI ↗

A large-scale binding and functional map of human RNA-binding proteins.

Nature · 2020 · 583(7818): 711-719

Many proteins regulate the expression of genes by binding to specific regions encoded in the genome¹. Here we introduce a new data set of RNA elements in the human genome that are recognized by RNA-binding proteins (RBPs), generated as part …

PMID 32728246 DOI ↗

Pooled CRISPR screens with imaging on microraft arrays reveals stress granule-regulatory factors.

Nature methods · 2020 · 17(6): 636-642

Genetic screens using pooled CRISPR-based approaches are scalable and inexpensive, but restricted to standard readouts, including survival, proliferation and sortable markers. However, many biologically relevant cell states involve cellular and subcellular changes that are only accessible by microscopic visualization, and …

PMID 32393832 DOI ↗

An in vivo genome-wide CRISPR screen identifies the RNA-binding protein Staufen2 as a key regulator of myeloid leukemia.

Nature cancer · 2020 · 1(4): 410-422

Aggressive myeloid leukemias such as blast crisis chronic myeloid leukemia and acute myeloid leukemia remain highly lethal. Here we report a genome-wide in vivo CRISPR screen to identify new dependencies in this disease. Among these, RNA-binding proteins (RBPs) in general, …

PMID 34109316 DOI ↗

How RNA-Binding Proteins Interact with RNA: Molecules and Mechanisms.

Molecular cell · 2020 · 78(1): 9-29

RNA-binding proteins (RBPs) comprise a large class of over 2,000 proteins that interact with transcripts in all manner of RNA-driven processes. The structures and mechanisms that RBPs use to bind and regulate RNA are incredibly diverse. In this review, we …

PMID 32243832 DOI ↗

Regulation of RNA editing by RNA-binding proteins in human cells.

Communications biology · 2019 · 2: 19

Adenosine-to-inosine (A-to-I) editing, mediated by the ADAR enzymes, diversifies the transcriptome by altering RNA sequences. Recent studies reported global changes in RNA editing in disease and development. Such widespread editing variations necessitate an improved understanding of the regulatory mechanisms of …

PMID 30652130 DOI ↗

Small-Molecule Modulation of TDP-43 Recruitment to Stress Granules Prevents Persistent TDP-43 Accumulation in ALS/FTD.

Neuron · 2019 · 103(5): 802-819.e11

Stress granules (SGs) form during cellular stress and are implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). To yield insights into the role of SGs in pathophysiology, we performed a high-content screen to identify small …

PMID 31272829 DOI ↗

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

Cell · 2019 · 178(1): 107-121.e18

Increasing evidence suggests that transcriptional control and chromatin activities at large involve regulatory RNAs, which likely enlist specific RNA-binding proteins (RBPs). Although multiple RBPs have been implicated in transcription control, it has remained unclear how extensively RBPs directly act on …

PMID 31251911 DOI ↗

Allele-specific binding of RNA-binding proteins reveals functional genetic variants in the RNA.

Nature communications · 2019 · 10(1): 1338

Allele-specific protein-RNA binding is an essential aspect that may reveal functional genetic variants (GVs) mediating post-transcriptional regulation. Recently, genome-wide detection of in vivo binding of RNA-binding proteins is greatly facilitated by the enhanced crosslinking and immunoprecipitation (eCLIP) method. We developed …

PMID 30902979 DOI ↗

NEAT1 scaffolds RNA-binding proteins and the Microprocessor to globally enhance pri-miRNA processing.

Nature structural & molecular biology · 2017 · 24(10): 816-824

MicroRNA (miRNA) biogenesis is known to be modulated by a variety of RNA-binding proteins (RBPs), but in most cases, individual RBPs appear to influence the processing of a small subset of target miRNAs. Here, we report that the RNA-binding NONO-PSF …

PMID 28846091 DOI ↗

Genetic mutations in RNA-binding proteins and their roles in ALS.

Human genetics · 2017 · 136(9): 1193-1214

Mutations in genes that encode RNA-binding proteins (RBPs) have emerged as critical determinants of neurological diseases, especially motor neuron disorders such as amyotrophic lateral sclerosis (ALS). RBPs are involved in all aspects of RNA processing, controlling the life cycle of …

PMID 28762175 DOI ↗

Experimental and Computational Considerations in the Study of RNA-Binding Protein-RNA Interactions.

Advances in experimental medicine and biology · 2016 · 907: 1-28

After an RNA is transcribed, it undergoes a variety of processing steps that can change the encoded protein sequence (through alternative splicing and RNA editing), regulate the stability of the RNA, and control subcellular localization, timing, and rate of translation. …

PMID 27256380 DOI ↗