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Gain-of-function cardiomyopathic mutations in RBM20 rewire splicing regulation and re-distribute ribonucleoprotein granules within processing bodies.

Nature communications · 2021 · 12(1): 6324

Mutations in the cardiac splicing factor RBM20 lead to malignant dilated cardiomyopathy (DCM). To understand the mechanism of RBM20-associated DCM, we engineered isogenic iPSCs with DCM-associated missense mutations in RBM20 as well as RBM20 knockout (KO) iPSCs. iPSC-derived engineered heart …

PMID 34732726 DOI ↗

Persistent mRNA localization defects and cell death in ALS neurons caused by transient cellular stress.

Cell reports · 2021 · 36(10): 109685

Persistent cytoplasmic aggregates containing RNA binding proteins (RBPs) are central to the pathogenesis of late-onset neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). These aggregates share components, molecular mechanisms, and cellular protein quality control pathways with stress-induced RNA granules (SGs). …

PMID 34496257 DOI ↗

Non-microRNA binding competitively inhibits LIN28 regulation.

Cell reports · 2021 · 36(6): 109517

RNA binding protein (RBP) expression is finite. For RBPs that are vastly outnumbered by their potential target sites, a simple competition for binding can set the magnitude of post-transcriptional control. Here, we show that LIN28, best known for its direct …

PMID 34380031 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 ↗

The <i>Thermus thermophilus</i> DEAD-box protein Hera is a general RNA binding protein and plays a key role in tRNA metabolism.

RNA (New York, N.Y.) · 2020 · 26(11): 1557-1574

RNA helicases catalyze the ATP-dependent destabilization of RNA duplexes. DEAD-box helicases share a helicase core that mediates ATP binding and hydrolysis, RNA binding and unwinding. Most members of this family contain domains flanking the core that can confer RNA substrate …

PMID 32669294 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 ↗

Evaluation of Engineered CRISPR-Cas-Mediated Systems for Site-Specific RNA Editing.

Cell reports · 2020 · 33(5): 108350

Site-directed RNA editing approaches offer great potential to correct genetic mutations in somatic cells while avoiding permanent off-target genomic edits. Nuclease-dead RNA-targeting CRISPR-Cas systems recruit functional effectors to RNA molecules in a programmable fashion. Here, we demonstrate a Streptococcus pyogenes …

PMID 33147453 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 ↗

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 ↗

Transcriptome-wide analysis of PGC-1α-binding RNAs identifies genes linked to glucagon metabolic action.

Proceedings of the National Academy of Sciences of the United States of America · 2020 · 117(36): 22204-22213

The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a transcriptional coactivator that controls expression of metabolic/energetic genes, programming cellular responses to nutrient and environmental adaptations such as fasting, cold, or exercise. Unlike other coactivators, PGC-1α contains protein domains involved …

PMID 32848060 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 ↗

Principles of RNA processing from analysis of enhanced CLIP maps for 150 RNA binding proteins.

Genome biology · 2020 · 21(1): 90

A critical step in uncovering rules of RNA processing is to study the in vivo regulatory networks of RNA binding proteins (RBPs). Crosslinking and immunoprecipitation (CLIP) methods enable mapping RBP targets transcriptome-wide, but methodological differences present challenges to large-scale analysis …

PMID 32252787 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 ↗