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RNA-targeting CRISPR systems from metagenomic discovery to transcriptomic engineering.

Nature cell biology · 2020 · 22(2): 143-150

Deployment of RNA-guided DNA endonuclease CRISPR-Cas technology has led to radical advances in biology. As the functional diversity of CRISPR-Cas and parallel systems is further explored, RNA manipulation is emerging as a powerful mode of CRISPR-based engineering. In this Perspective, …

PMID 32015437 DOI ↗

Direct RNA sequencing enables m⁶A detection in endogenous transcript isoforms at base-specific resolution.

RNA (New York, N.Y.) · 2020 · 26(1): 19-28

Direct RNA sequencing holds great promise for the de novo identification of RNA modifications at single-coordinate resolution; however, interpretation of raw sequencing output to discover modified bases remains a challenge. Using Oxford Nanopore's direct RNA sequencing technology, we developed a …

PMID 31624092 DOI ↗

Longitudinal assessment of tumor development using cancer avatars derived from genetically engineered pluripotent stem cells.

Nature communications · 2020 · 11(1): 550

Many cellular models aimed at elucidating cancer biology do not recapitulate pathobiology including tumor heterogeneity, an inherent feature of cancer that underlies treatment resistance. Here we introduce a cancer modeling paradigm using genetically engineered human pluripotent stem cells (hiPSCs) that …

PMID 31992716 DOI ↗

Corrigendum: Patch-Seq Protocol to Analyze the Electrophysiology, Morphology and Transcriptome of Whole Single Neurons Derived From Human Pluripotent Stem Cells.

Frontiers in molecular neuroscience · 2019 · 12: 150

[This corrects the article DOI: 10.3389/fnmol.2018.00261.].

PMID 31244603 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 ↗

The RNA Helicase DDX6 Controls Cellular Plasticity by Modulating P-Body Homeostasis.

Cell stem cell · 2019 · 25(5): 622-638.e13

Post-transcriptional mechanisms have the potential to influence complex changes in gene expression, yet their role in cell fate transitions remains largely unexplored. Here, we show that suppression of the RNA helicase DDX6 endows human and mouse primed embryonic stem cells …

PMID 31588046 DOI ↗

Peptide Brush Polymers for Efficient Delivery of a Gene Editing Protein to Stem Cells.

Angewandte Chemie (International ed. in English) · 2019 · 58(44): 15646-15649

The scarcity of effective means to deliver functional proteins to living cells is a central problem in biotechnology and medicine. Herein, we report the efficient delivery of an active DNA-modifying enzyme to human stem cells through high-density cell penetrating peptide …

PMID 31404473 DOI ↗

Complex Oscillatory Waves Emerging from Cortical Organoids Model Early Human Brain Network Development.

Cell stem cell · 2019 · 25(4): 558-569.e7

Structural and transcriptional changes during early brain maturation follow fixed developmental programs defined by genetics. However, whether this is true for functional network activity remains unknown, primarily due to experimental inaccessibility of the initial stages of the living human brain. …

PMID 31474560 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 ↗

Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson's Disease.

Cell stem cell · 2019 · 24(6): 1006

PMID 31173705 DOI ↗

Active Protein Neddylation or Ubiquitylation Is Dispensable for Stress Granule Dynamics.

Cell reports · 2019 · 27(5): 1356-1363.e3

Stress granule (SG) formation is frequently accompanied by ubiquitin proteasome system (UPS) impairment and ubiquitylated protein accumulation. SGs, ubiquitin, and UPS components co-localize, but the relationship between the ubiquitin pathway and SGs has not been systematically characterized. We utilize pharmacological …

PMID 31042464 DOI ↗

Disruption in A-to-I Editing Levels Affects C. elegans Development More Than a Complete Lack of Editing.

Cell reports · 2019 · 27(4): 1244-1253.e4

A-to-I RNA editing, catalyzed by ADAR proteins, is widespread in eukaryotic transcriptomes. Studies showed that, in C. elegans, ADR-2 can actively deaminate dsRNA, whereas ADR-1 cannot. Therefore, we set out to study the effect of each of the ADAR genes …

PMID 31018137 DOI ↗

Glial cells maintain synapses by inhibiting an activity-dependent retrograde protease signal.

PLoS genetics · 2019 · 15(3): e1007948

Glial cells regulate multiple aspects of synaptogenesis. In the absence of Schwann cells, a peripheral glial cell, motor neurons initially innervate muscle but then degenerate. Here, using a genetic approach, we show that neural activity-regulated negative factors produced by muscle …

PMID 30870413 DOI ↗

A Transcriptome-wide Translational Program Defined by LIN28B Expression Level.

Molecular cell · 2019 · 73(2): 304-313.e3

LIN28 RNA binding proteins are dynamically expressed throughout mammalian development and during disease. However, it remains unclear how changes in LIN28 expression define patterns of post-transcriptional gene regulation. Here we show that LIN28 expression level is a key variable that …

PMID 30527666 DOI ↗

Patch-Seq Protocol to Analyze the Electrophysiology, Morphology and Transcriptome of Whole Single Neurons Derived From Human Pluripotent Stem Cells.

Frontiers in molecular neuroscience · 2018 · 11: 261

The human brain is composed of a complex assembly of about 171 billion heterogeneous cellular units (86 billion neurons and 85 billion non-neuronal glia cells). A comprehensive description of brain cells is necessary to understand the nervous system in health …

PMID 30147644 DOI ↗

Transcriptome-pathology correlation identifies interplay between TDP-43 and the expression of its kinase CK1E in sporadic ALS.

Acta neuropathologica · 2018 · 136(3): 405-423

Sporadic amyotrophic lateral sclerosis (sALS) is the most common form of ALS, however, the molecular mechanisms underlying cellular damage and motor neuron degeneration remain elusive. To identify molecular signatures of sALS we performed genome-wide expression profiling in laser capture microdissection-enriched …

PMID 29881994 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 ↗

Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson's Disease.

Cell stem cell · 2018 · 23(1): 123-131.e6

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of midbrain neurons (MBNs). Recent evidence suggests contribution of the adaptive immune system in PD. Here, we show a role for human T lymphocytes as cell death inducers …

PMID 29979986 DOI ↗

Sequence, Structure, and Context Preferences of Human RNA Binding Proteins.

Molecular cell · 2018 · 70(5): 854-867.e9

RNA binding proteins (RBPs) orchestrate the production, processing, and function of mRNAs. Here, we present the affinity landscapes of 78 human RBPs using an unbiased assay that determines the sequence, structure, and context preferences of these proteins in vitro by …

PMID 29883606 DOI ↗

Systematic Discovery of RNA Binding Proteins that Regulate MicroRNA Levels.

Molecular cell · 2018 · 69(6): 1005-1016.e7

RNA binding proteins (RBPs) interact with primary, precursor, and mature microRNAs (miRs) to influence mature miR levels, which in turn affect critical aspects of human development and disease. To understand how RBPs contribute to miR biogenesis, we analyzed human enhanced …

PMID 29547715 DOI ↗

Advances and challenges in the detection of transcriptome-wide protein-RNA interactions.

Wiley interdisciplinary reviews. RNA · 2018 · 9(1)

RNA binding proteins (RBPs) play key roles in determining cellular behavior by manipulating the processing of target RNAs. Robust methods are required to detect the numerous binding sites of RBPs across the transcriptome. RNA-immunoprecipitation followed by sequencing (RIP-seq) and crosslinking …

PMID 28853213 DOI ↗

Context-Dependent and Disease-Specific Diversity in Protein Interactions within Stress Granules.

Cell · 2018 · 172(3): 590-604.e13

Stress granules (SGs) are transient ribonucleoprotein (RNP) aggregates that form during cellular stress and are increasingly implicated in human neurodegeneration. To study the proteome and compositional diversity of SGs in different cell types and in the context of neurodegeneration-linked mutations, …

PMID 29373831 DOI ↗

Self-Transfecting Micellar RNA: Modulating Nanoparticle Cell Interactions via High Density Display of Small Molecule Ligands on Micelle Coronas.

Bioconjugate chemistry · 2018 · 29(1): 126-135

The intracellular delivery of synthetic nucleic acids represents a major challenge in biotechnology and in biomedicine. Methods to deliver short, double-stranded RNA to living cells are of particular interest because of the potential to engage the RNA interference machinery and …

PMID 29286237 DOI ↗

Short poly(A) tails are a conserved feature of highly expressed genes.

Nature structural & molecular biology · 2017 · 24(12): 1057-1063

Poly(A) tails are important elements in mRNA translation and stability, although recent genome-wide studies have concluded that poly(A) tail length is generally not associated with translational efficiency in nonembryonic cells. To investigate whether poly(A) tail size might be coupled to …

PMID 29106412 DOI ↗