Search publications

Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis.

Acta neuropathologica · 2022 · 144(3): 413-435

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by aberrant alternative splicing (AS). Nuclear loss and cytoplasmic accumulation of the splicing factor TDP-43 in motor neurons (MN) are hallmarks of ALS at late stages of the disease. However, it …

PMID 35778567 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 ↗

Nuclear and cytoplasmic poly(A) binding proteins (PABPs) favor distinct transcripts and isoforms.

Nucleic acids research · 2022 · 50(8): 4685-4702

The poly(A)-tail appended to the 3'-end of most eukaryotic transcripts plays a key role in their stability, nuclear transport, and translation. These roles are largely mediated by Poly(A) Binding Proteins (PABPs) that coat poly(A)-tails and interact with various proteins involved …

PMID 35438785 DOI ↗

Integrative RNA-omics Discovers GNAS Alternative Splicing as a Phenotypic Driver of Splicing Factor-Mutant Neoplasms.

Cancer discovery · 2022 · 12(3): 836-855

Mutations in splicing factors (SF) are the predominant class of mutations in myelodysplastic syndrome (MDS), but convergent downstream disease drivers remain elusive. To identify common direct targets of missplicing by mutant U2AF1 and SRSF2, we performed RNA sequencing and enhanced …

PMID 34620690 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 ↗

A multi-scale map of cell structure fusing protein images and interactions.

Nature · 2021 · 600(7889): 536-542

The cell is a multi-scale structure with modular organization across at least four orders of magnitude¹. Two central approaches for mapping this structure-protein fluorescent imaging and protein biophysical association-each generate extensive datasets, but of distinct qualities and resolutions that are …

PMID 34819669 DOI ↗

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 ↗

ADAR and hnRNPC deficiency synergize in activating endogenous dsRNA-induced type I IFN responses.

The Journal of experimental medicine · 2021 · 218(9)

Cytosolic double-stranded RNA (dsRNA) initiates type I IFN responses. Endogenous retroelements, notably Alu elements, constitute a source of dsRNA. Adenosine-to-inosine (A-to-I) editing by ADAR induces mismatches in dsRNA and prevents recognition by MDA5 and autoinflammation. To identify additional endogenous dsRNA …

PMID 34297039 DOI ↗

Loss of LUC7L2 and U1 snRNP subunits shifts energy metabolism from glycolysis to OXPHOS.

Molecular cell · 2021 · 81(9): 1905-1919.e12

Oxidative phosphorylation (OXPHOS) and glycolysis are the two major pathways for ATP production. The reliance on each varies across tissues and cell states, and can influence susceptibility to disease. At present, the full set of molecular mechanisms governing the relative …

PMID 33852893 DOI ↗

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

Genes & development · 2021 · 35(5-6): 425

PMID 33649163 DOI ↗

The sustained expression of Cas9 targeting toxic RNAs reverses disease phenotypes in mouse models of myotonic dystrophy type 1.

Nature biomedical engineering · 2021 · 5(2): 157-168

Myotonic dystrophy type I (DM1) is a multisystemic autosomal-dominant inherited human disorder that is caused by CTG microsatellite repeat expansions (MREs) in the 3' untranslated region of DMPK. Toxic RNAs expressed from such repetitive sequences can be eliminated using CRISPR-mediated …

PMID 32929188 DOI ↗

Reintroduction of the archaic variant of <i>NOVA1</i> in cortical organoids alters neurodevelopment.

Science (New York, N.Y.) · 2021 · 371(6530)

The evolutionarily conserved splicing regulator neuro-oncological ventral antigen 1 (<i>NOVA1</i>) plays a key role in neural development and function. <i>NOVA1</i> also includes a protein-coding difference between the modern human genome and Neanderthal and Denisovan genomes. To investigate the functional importance …

PMID 33574182 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 ↗

Context-dependent functional compensation between Ythdf m⁶A reader proteins.

Genes & development · 2020 · 34(19-20): 1373-1391

The N6-methyladenosine (m⁶A) modification is the most prevalent post-transcriptional mRNA modification, regulating mRNA decay and splicing. It plays a major role during normal development, differentiation, and disease progression. The modification is regulated by a set of writer, eraser, and reader …

PMID 32943573 DOI ↗

Motoneuron expression profiling identifies an association between an axonal splice variant of HDGF-related protein 3 and peripheral myelination.

The Journal of biological chemistry · 2020 · 295(34): 12233-12246

Disorders that disrupt myelin formation during development or in adulthood, such as multiple sclerosis and peripheral neuropathies, lead to severe pathologies, illustrating myelin's crucial role in normal neural functioning. However, although our understanding of glial biology is increasing, the signals …

PMID 32647008 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 ↗

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 ↗

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 ↗

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 ↗

Disruption of RNA Metabolism in Neurological Diseases and Emerging Therapeutic Interventions.

Neuron · 2019 · 102(2): 294-320

RNA binding proteins are critical to the maintenance of the transcriptome via controlled regulation of RNA processing and transport. Alterations of these proteins impact multiple steps of the RNA life cycle resulting in various molecular phenotypes such as aberrant RNA …

PMID 30998900 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 ↗

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 ↗