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Mutant FUS and ELAVL4 (HuD) aberrant crosstalk in Amyotrophic Lateral Sclerosis

ABSTRACT: Determination of RNAs bound by wildtype and P525L mutant FUS in human iPSC-derived motoneurons using PAR-CLIP (Photoactivatable Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation)

ORGANISM(S): Homo sapiens

PROVIDER: GSE118347 | GEO | 2019/06/13

REPOSITORIES: GEO

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Mutant FUS and ELAVL4 (HuD) Aberrant Crosstalk in Amyotrophic Lateral Sclerosis.

Project description:Amyotrophic lateral sclerosis (ALS) has been genetically linked to mutations in RNA-binding proteins (RBPs), including FUS. Here, we report the RNA interactome of wild-type and mutant FUS in human motor neurons (MNs). This analysis identified a number of RNA targets. Whereas the wild-type protein preferentially binds introns, the ALS mutation causes a shift toward 3' UTRs. Neural ELAV-like RBPs are among mutant FUS targets. As a result, ELAVL4 protein levels are increased in mutant MNs. ELAVL4 and mutant FUS interact and co-localize in cytoplasmic speckles with altered biomechanical properties. Upon oxidative stress, ELAVL4 and mutant FUS are engaged in stress granules. In the spinal cord of FUS ALS patients, ELAVL4 represents a neural-specific component of FUS-positive cytoplasmic aggregates, whereas in sporadic patients it co-localizes with phosphorylated TDP-43-positive inclusions. We propose that pathological mutations in FUS trigger an aberrant crosstalk with ELAVL4 with implications for ALS.

| S-EPMC6613039 | biostudies-literature

Mutant FUS and ELAVL4 (HuD) aberrant crosstalk in Amyotrophic Lateral Sclerosis

Project description:Mutant FUS and ELAVL4 (HuD) aberrant crosstalk in Amyotrophic Lateral Sclerosis

| PRJNA485313 | ENA

RNA-seq to investigate the phase separation-dependent FUS RNA interactome

Project description:The protein Fused in Sarcoma undergoes liquid-liquid phase separation. To investigate whether this phase transition alters the RNA interactome we purified phase-separated FUS droplets and soluble FUS from HEK 293T cells transfected with GFP-tagged WT FUS or P525L FUS. Phase separated FUS was purified by fluorescence-activated particle sorting (droplets) and soluble FUS by co-Immunoprecipitation (IP) respectively followed by isolation of co-purified RNA. Here we show that phase separation affects the RNA interactome of FUS.

2021-06-23 | E-MTAB-8456 | biostudies-arrayexpress

Yeast mitochondrial protein Pet111p binds directly to two distinct targets in COX2 mRNA, suggesting a mechanism of translational activation.

Project description:Genome-wide RNA binding profile of Pet111p by photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) confirmed that Pet111p preferentially associates with the 5'-end proximal portion of COX2 mRNA.

2019-03-20 | GSE117899 | GEO

A study of how homozygous ALS-linked FUS P525L mutations perturb transcriptome profile in human iPSC-derived microglia

Project description:Purpose: The FUS P525L mutation is highly penetrant and causes ALS cases with earlier disease onset and more aggressive progression. This study aims to understand the impact of P525L mutations in microglia during ALS pathogenesis. We compare the transcriptome (RNA-seq) of P525L mutations to the wildtype and isogenic controls to derive the differentially perturbed genes. Methods: Transcriptome profiles of human iPSC-derived microglia with gentoype of wild-type (WT), isogenic control (eCtrl), P525L homozygous (P525LHom), P525L heterozygous (P252LHet) and null deletion (KO) were generated using Illumina HiSeq2000 by multiplexed paired-read run with 100 cycles. Pass-QC sequencing reads were mapped to the human genome (hg19) using the OmicSoft ArrayStudio software followed by differential gene expression analysis via DESeq2 package. Results: Homozygous P525L mutations perturb the transcriptome profile where many differentially expressed genes are associated with microglial functions. Specifically, dysregulation of several chemoreceptor genes leads to altered chemoreceptor-activated calcium signaling. Conclusions: Our study underscores the cell- autonomous effects of the ALS-linked FUS P525L mutation in a human microglia model.

2022-02-03 | GSE172459 | GEO

Identification of Nucleolin-binding targets and sequences in LPS-stimulated RAW 264.7 cells by PAR-CLIP

Project description:To investigate the consensus RNA-binding motifs of Nucleoli, we performed photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) analysis in nucleolar fractions from unstimulated or 12 h LPS-stimulated RAW 264.7 cells

2022-09-15 | GSE211163 | GEO

Project description:Mutations in the RNA-binding protein (RBP) FUS have been genetically associated with the motoneuron disease amyotrophic lateral sclerosis (ALS). Using both human induced pluripotent stem cells and mouse models, we found that FUS-ALS causative mutations affect the activity of two relevant RBPs with important roles in neuronal RNA metabolism: HuD/ELAVL4 and FMRP. Mechanistically, mutant FUS leads to upregulation of HuD protein levels through competition with FMRP for HuD mRNA 3'UTR binding. In turn, increased HuD levels overly stabilize the transcript levels of its targets, NRN1 and GAP43. As a consequence, mutant FUS motoneurons show increased axon branching and growth upon injury, which could be rescued by dampening NRN1 levels. Since similar phenotypes have been previously described in SOD1 and TDP-43 mutant models, increased axonal growth and branching might represent broad early events in the pathogenesis of ALS.

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The FUS protein participates in circRNA biogenesis

Project description:The RNA binding protein FUS exerts its function in several RNA biosynthetic processes; moreover, mutations leading to changes in its expression levels or alterations in cellular compartmentalization have been linked to the pathogenesis of Amyotrophic Lateral Sclerosis. Here, we describe an additional novel function of FUS, that is the control of back-splicing reactions which lead to circular RNA (circRNA) production. We identified circRNAs expressed in murine ES-derived motoneurons and then compared their levels in control versus FUS-/- cells. We discovered that a considerable number of circRNAs is affected by FUS levels.

2017-02-27 | GSE83226 | GEO

Transcriptome-wide identification of nuclear and cytoplasmic RNA-binding sites of FUS RBD-only constructs

Project description:We report the binding sites of three FUS constructs: (1) The full-length protein (FL); (2) A deletion mutant consisting of amino acids 242-526 (CT); and (3) A aa 242-526 deletion mutant with ALS-associated P525L mutation and heterologous nuclear export signal (CTstar) with the aim to assess the role of protein-protein interactions on RNA-binding and to identify nuclear and cytoplasmic RNA-binding sites of Fused in Sarcoma (FUS).

2020-10-21 | GSE139263 | GEO

NONO knockdown RNA-seq and neuroblastoma PARCLIP analysis of NONO

Project description:siRNA knockdown of NONO mRNA followed by RNA-seq was carried out in the KELLY neuroblasotma cell line. In order to determine potential regulatory targets of NONO protein, we performed differential expression analysis. To identify the RNA targets of NONO in neuroblastoma, we carried out PAR-CLIP (Photoactivatable Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation) using an antibody recognising NONO protein.

2023-01-28 | GSE114376 | GEO

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