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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 ↗

Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis.

eLife · 2019 · 8

Mutations in coding and non-coding regions of FUS cause amyotrophic lateral sclerosis (ALS). The latter mutations may exert toxicity by increasing FUS accumulation. We show here that broad expression within the nervous system of wild-type or either of two ALS-linked …

PMID 30747709 DOI ↗

Widespread RNA editing dysregulation in brains from autistic individuals.

Nature neuroscience · 2019 · 22(1): 25-36

Transcriptomic analyses of postmortem brains have begun to elucidate molecular abnormalities in autism spectrum disorder (ASD). However, a crucial pathway involved in synaptic development, RNA editing, has not yet been studied on a genome-wide scale. Here we profiled global patterns …

PMID 30559470 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 ↗

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 ↗

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 ↗

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 ↗

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 ↗

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 ↗

Robust, Cost-Effective Profiling of RNA Binding Protein Targets with Single-end Enhanced Crosslinking and Immunoprecipitation (seCLIP).

Methods in molecular biology (Clifton, N.J.) · 2017 · 1648: 177-200

Profiling of RNA binding protein targets in vivo provides critical insights into the mechanistic roles they play in regulating RNA processing. The enhanced crosslinking and immunoprecipitation (eCLIP) methodology provides a framework for robust, reproducible identification of transcriptome-wide protein-RNA interactions, with …

PMID 28766298 DOI ↗

Erratum to: Robust, Cost-Effective Profiling of RNA Binding Protein Targets with Single-end Enhanced Crosslinking and Immunoprecipitation (seCLIP).

Methods in molecular biology (Clifton, N.J.) · 2017 · 1648: E1

PMID 29230720 DOI ↗

Nol12 is a multifunctional RNA binding protein at the nexus of RNA and DNA metabolism.

Nucleic acids research · 2017 · 45(21): 12509-12528

To counteract the breakdown of genome integrity, eukaryotic cells have developed a network of surveillance pathways to prevent and resolve DNA damage. Recent data has recognized the importance of RNA binding proteins (RBPs) in DNA damage repair (DDR) pathways. Here, …

PMID 29069457 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 ↗

The <i>C. elegans</i> neural editome reveals an ADAR target mRNA required for proper chemotaxis.

eLife · 2017 · 6

ADAR proteins alter gene expression both by catalyzing adenosine (A) to inosine (I) RNA editing and binding to regulatory elements in target RNAs. Loss of ADARs affects neuronal function in all animals studied to date. <i>Caenorhabditis elegans</i> lacking ADARs exhibit …

PMID 28925356 DOI ↗

Elimination of Toxic Microsatellite Repeat Expansion RNA by RNA-Targeting Cas9.

Cell · 2017 · 170(5): 899-912.e10

Microsatellite repeat expansions in DNA produce pathogenic RNA species that cause dominantly inherited diseases such as myotonic dystrophy type 1 and 2 (DM1/2), Huntington's disease, and C9orf72-linked amyotrophic lateral sclerosis (C9-ALS). Means to target these repetitive RNAs are required for …

PMID 28803727 DOI ↗

Variation in single-nucleotide sensitivity of eCLIP derived from reverse transcription conditions.

Methods (San Diego, Calif.) · 2017 · 126: 29-37

Crosslinking and immunoprecipitation (CLIP) followed by high-throughput sequencing identifies the binding sites of RNA binding proteins on RNAs. The covalent RNA-amino acid adducts produced by UV irradiation can cause premature reverse transcription termination and deletions (referred to as crosslink-induced mutation …

PMID 28790018 DOI ↗

Pseudotemporal Ordering of Single Cells Reveals Metabolic Control of Postnatal β Cell Proliferation.

Cell metabolism · 2017 · 25(5): 1160-1175.e11

Pancreatic β cell mass for appropriate blood glucose control is established during early postnatal life. β cell proliferative capacity declines postnatally, but the extrinsic cues and intracellular signals that cause this decline remain unknown. To obtain a high-resolution map of …

PMID 28467932 DOI ↗

Interaction Landscape of Inherited Polymorphisms with Somatic Events in Cancer.

Cancer discovery · 2017 · 7(4): 410-423

Recent studies have characterized the extensive somatic alterations that arise during cancer. However, the somatic evolution of a tumor may be significantly affected by inherited polymorphisms carried in the germline. Here, we analyze genomic data for 5,954 tumors to reveal …

PMID 28188128 DOI ↗

Early transcriptional and epigenetic regulation of CD8⁺ T cell differentiation revealed by single-cell RNA sequencing.

Nature immunology · 2017 · 18(4): 422-432

During microbial infection, responding CD8⁺ T lymphocytes differentiate into heterogeneous subsets that together provide immediate and durable protection. To elucidate the dynamic transcriptional changes that underlie this process, we applied a single-cell RNA-sequencing approach and analyzed individual CD8⁺ T lymphocytes …

PMID 28218746 DOI ↗

CRISPR/Cas9-mediated integration enables TAG-eCLIP of endogenously tagged RNA binding proteins.

Methods (San Diego, Calif.) · 2017 · 118-119: 50-59

Identification of in vivo direct RNA targets for RNA binding proteins (RBPs) provides critical insight into their regulatory activities and mechanisms. Recently, we described a methodology for enhanced crosslinking and immunoprecipitation followed by high-throughput sequencing (eCLIP) using antibodies against endogenous …

PMID 28003131 DOI ↗