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Large-scale tethered screen of RNA-binding proteins reveals novel regulators of poly(A) site selection.

Molecular cell · 2026

Alternative polyadenylation (APA) generates transcript isoforms with distinct 3' ends, yet the repertoire of its protein regulators remains poorly defined. Using a large-scale tethered function screen, we profiled 879 human RNA-binding proteins (RBPs) and identified 63 high-confidence activators of poly(A) …

PMID 42361791 DOI ↗

Integrative CRISPR Screening and RNA Analyses Discover an Essential Role for PUF60 Interactions with 3' Splice Sites in Cancer Progression.

Cancer research · 2025

RNA-binding proteins (RBPs) are important regulators of post-transcriptional gene expression. Understanding which and how RBPs promote cancer progression is crucial for cancers that lack effective targeted therapies, such as triple negative breast cancer (TNBC). Here, we employed both in vitro …

PMID 41411621 DOI ↗

Dual-targeting snRNA gene therapy rescues STMN2 and UNC13A splicing in TDP-43 proteinopathies.

bioRxiv : the preprint server for biology · 2025

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by the selective deterioration of motor neurons in the central nervous system (CNS). A key driver of this pathogenesis is nuclear loss of ALS-associated protein TDP-43, leading to mis-splicing of TDP-43 …

PMID 41573891 DOI ↗

Dosage-sensitive <i>RBFOX2</i> autoregulation promotes cardiomyocyte differentiation by maturing the transcriptome.

bioRxiv : the preprint server for biology · 2025

Haploinsufficiency of the RNA splicing regulator, <i>RBFOX2</i> , is linked to congenital heart disease (CHD), yet its pathogenic mechanisms remain unclear. Here, we demonstrate that RBFOX2 is essential for progressing cardiomyocyte (CM) differentiation by shifting exon usage profiles to more …

PMID 41280054 DOI ↗

A splice-switching antisense oligonucleotide approach for pediatric genetic epilepsies.

bioRxiv : the preprint server for biology · 2025

Variants in ion channel genes are common causes of pediatric epilepsy, often leading to intractable seizures, developmental delay and other comorbidities, which increases risk of death. Pathogenic variants in the <i>SCN8A</i> gene, which encodes a voltage-gated sodium channel critical for …

PMID 41278710 DOI ↗

Enhancing RNA base editing on mammalian transcripts with small nuclear RNAs.

Nature chemical biology · 2025

Endogenous uridine-rich small nuclear RNAs (U snRNAs) form RNA-protein complexes to process eukaryotic pre-mRNA into mRNA. Previous studies have demonstrated programmable U snRNA guide-targeted exon inclusion and exclusion. Here we investigated whether snRNAs can also enhance RNA base editing over …

PMID 40968292 DOI ↗

Integrative CRISPR Screens and RNA-Omics Discover an Essential Role for PUF60-3' Splice Site Interactions in Cancer Progression.

bioRxiv : the preprint server for biology · 2025

RNA-binding proteins (RBPs) are important regulators of post-transcriptional gene expression. Understanding which and how RBPs promote cancer progression is crucial for cancers that lack effective targeted therapies such as triple negative breast cancer (TNBC). Here, we employ both <i>in vitro</i> …

PMID 40655003 DOI ↗

Large-scale evaluation of the ability of RNA-binding proteins to activate exon inclusion.

Nature biotechnology · 2024 · 42(9): 1429-1441

RNA-binding proteins (RBPs) modulate alternative splicing outcomes to determine isoform expression and cellular survival. To identify RBPs that directly drive alternative exon inclusion, we developed tethered function luciferase-based splicing reporters that provide rapid, scalable and robust readouts of exon inclusion …

PMID 38168984 DOI ↗

Author Correction: Large-scale evaluation of the ability of RNA-binding proteins to activate exon inclusion.

Nature biotechnology · 2024 · 42(9): 1467

PMID 38418649 DOI ↗

Small nuclear RNAs enhance protein-free RNA-programmable base conversion on mammalian coding transcripts.

bioRxiv : the preprint server for biology · 2024

Endogenous U small nuclear RNAs (U snRNAs) form RNA-protein complexes responsible for eukaryotic processing of pre-mRNA into mature mRNA. Previous studies have demonstrated the utility of guide-programmable U snRNAs in targeted exon inclusion and exclusion. We investigated whether snRNAs can …

PMID 38915553 DOI ↗

An RNA-targeting CRISPR-Cas13d system alleviates disease-related phenotypes in Huntington's disease models.

Nature neuroscience · 2023 · 26(1): 27-38

Huntington's disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by CAG trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Since the reduction of pathogenic mutant HTT messenger RNA is therapeutic, we developed a mutant allele-sensitive CAG^EX …

PMID 36510111 DOI ↗

Metadensity: a background-aware python pipeline for summarizing CLIP signals on various transcriptomic sites.

Bioinformatics advances · 2022 · 2(1): vbac083

Cross-linking and immunoprecipitation (CLIP) is a technology to map the binding sites of RNA-binding proteins (RBPs). The region where an RBP binds within RNA is often indicative of its molecular function in RNA processing. As an example, the binding sites …

PMID 36388152 DOI ↗

VPS13A and VPS13C Influence Lipid Droplet Abundance.

Contact (Thousand Oaks (Ventura County, Calif.)) · 2022 · 5: 25152564221125613

Lipid transfer proteins mediate the exchange of lipids between closely apposed membranes at organelle contact sites and play key roles in lipid metabolism, membrane homeostasis, and cellular signaling. A recently discovered novel family of lipid transfer proteins, which includes the …

PMID 36147729 DOI ↗

Engineered U1 snRNAs to modulate alternatively spliced exons.

Methods (San Diego, Calif.) · 2022 · 205: 140-148

Alternative splicing accounts for a considerable portion of transcriptomic diversity, as most protein-coding genes are spliced into multiple mRNA isoforms. However, errors in splicing patterns can give rise to mis-splicing with pathological consequences, such as the congenital diseases familial dysautonomia, …

PMID 35764245 DOI ↗

AKT constitutes a signal-promoted alternative exon-junction complex that regulates nonsense-mediated mRNA decay.

Molecular cell · 2022 · 82(15): 2779-2796.e10

Despite a long appreciation for the role of nonsense-mediated mRNA decay (NMD) in destroying faulty, disease-causing mRNAs and maintaining normal, physiologic mRNA abundance, additional effectors that regulate NMD activity in mammalian cells continue to be identified. Here, we describe a …

PMID 35675814 DOI ↗

The splicing factor RBM17 drives leukemic stem cell maintenance by evading nonsense-mediated decay of pro-leukemic factors.

Nature communications · 2022 · 13(1): 3833

Chemo-resistance in acute myeloid leukemia (AML) patients is driven by leukemic stem cells (LSCs) resulting in high rates of relapse and low overall survival. Here, we demonstrate that upregulation of the splicing factor, RBM17 preferentially marks and sustains LSCs and …

PMID 35781533 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 ↗

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 ↗

RBP-Maps enables robust generation of splicing regulatory maps.

RNA (New York, N.Y.) · 2019 · 25(2): 193-204

Alternative splicing of pre-messenger RNA transcripts enables the generation of multiple protein isoforms from the same gene locus, providing a major source of protein diversity in mammalian genomes. RNA binding proteins (RBPs) bind to RNA to control splice site choice …

PMID 30413564 DOI ↗

An important class of intron retention events in human erythroblasts is regulated by cryptic exons proposed to function as splicing decoys.

RNA (New York, N.Y.) · 2018 · 24(9): 1255-1265

During terminal erythropoiesis, the splicing machinery in differentiating erythroblasts executes a robust intron retention (IR) program that impacts expression of hundreds of genes. We studied IR mechanisms in the <i>SF3B1</i> splicing factor gene, which expresses ∼50% of its transcripts in …

PMID 29959282 DOI ↗

Tissue-selective restriction of RNA editing of CaV1.3 by splicing factor SRSF9.

Nucleic acids research · 2018 · 46(14): 7323-7338

Adenosine DeAminases acting on RNA (ADAR) catalyzes adenosine-to-inosine (A-to-I) conversion within RNA duplex structures. While A-to-I editing is often dynamically regulated in a spatial-temporal manner, the mechanisms underlying its tissue-selective restriction remain elusive. We have previously reported that transcripts of …

PMID 29733375 DOI ↗

Single-Cell Alternative Splicing Analysis with Expedition Reveals Splicing Dynamics during Neuron Differentiation.

Molecular cell · 2017 · 67(1): 148-161.e5

Alternative splicing (AS) generates isoform diversity for cellular identity and homeostasis in multicellular life. Although AS variation has been observed among single cells, little is known about the biological or evolutionary significance of such variation. We developed Expedition, a computational …

PMID 28673540 DOI ↗

Protein-RNA Networks Regulated by Normal and ALS-Associated Mutant HNRNPA2B1 in the Nervous System.

Neuron · 2016 · 92(4): 780-795

HnRNPA2B1 encodes an RNA binding protein associated with neurodegeneration. However, its function in the nervous system is unclear. Transcriptome-wide crosslinking and immunoprecipitation in mouse spinal cord discover UAGG motifs enriched within ∼2,500 hnRNP A2/B1 binding sites and an unexpected role …

PMID 27773581 DOI ↗

A novel splice-site mutation in ALS2 establishes the diagnosis of juvenile amyotrophic lateral sclerosis in a family with early onset anarthria and generalized dystonias.

PloS one · 2014 · 9(12): e113258

The diagnosis of childhood neurological disorders remains challenging given the overlapping clinical presentation across subgroups and heterogeneous presentation within subgroups. To determine the underlying genetic cause of a severe neurological disorder in a large consanguineous Pakistani family presenting with severe …

PMID 25474699 DOI ↗

Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges.

Nature structural & molecular biology · 2013 · 20(12): 1434-42

Alternative splicing (AS) enables programmed diversity of gene expression across tissues and development. We show here that binding in distal intronic regions (>500 nucleotides (nt) from any exon) by Rbfox splicing factors important in development is extensive and is an …

PMID 24213538 DOI ↗