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RNA-binding protein ELAVL4/HuD ameliorates Alzheimer's disease-related molecular changes in human iPSC-derived neurons

ABSTRACT: We generated ELAVL4 knockout (KO), overexpression (OE), and rescue human induced pluripotent stem cell-derived neurons to study the effect that ELAVL4 has on AD-related cellular phenotypes. To gain insight into the molecular cascades involved in neuronal ELAVL4 signaling, we then performed gene expression profiling analysis using data obtained from RNA-seq using triplicate samples for each condition

ORGANISM(S): Homo sapiens

PROVIDER: GSE202985 | GEO | 2022/07/26

REPOSITORIES: GEO

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RNA-binding protein ELAVL4/HuD ameliorates Alzheimer's disease-related molecular changes in human iPSC-derived neurons

Project description:RNA-binding protein ELAVL4/HuD ameliorates Alzheimer's disease-related molecular changes in human iPSC-derived neurons

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MicroRNA-sequencing from the striatum of ELAVL4 (HuD) KO mice and wild type littermate adult mice

Project description:Purpose: The goals of this study are to determine how deletion of the RNA-binding protein HuD affects the levels of microRNAs in the striatum of Elav4 (HuD) KO using miRNA-seq Methods: Total RNA from striatum of male adult Elavl4 (HuD) KO and wild-type (WT) littermates (n=3 per genotype) crossbred to C57Bl/6 for more than 10 generations were analyzed by small RNA sequencing, in triplicate, using an Illumina NextSeq platorm. The percentage of the number of bases with Q >30 for all 6 samples were >93%. Results: Using an optimized data analysis workflow (see diagram below), about 6.3 million sequence reads per HuD KO sample and 3.3 million per WT sample were mapped miRBase v22. The expression level (Reads count) of miRNAs were calculated using miRDeep2. The number of identified miRNA per group was calculated based on the mean of CPM in group > 1. Conclusions: We found 309 miRNAs from 54 unique families (FC>1.75- and p<0.05) were significantly upregulated while 161 miRNAs from 143 unique families (FC<0.55 and p<0.05) were significantly downregulated in the striatum of HuD KO mice vs WT samples.

2021-09-29 | GSE179652 | GEO

RNA Sequencing analyses of control and HuD KO (Elavl4 null) mouse cortical transcriptomes

Project description:Purpose: The goal of this study was to analyse RNA-seq data to determine the effect of deletion of the RNA-binding protein HuD in transcriptiome-wide alternative splicing and polyadenylation in the neocortex of adult HuD KO vs. wild type littermates (controls) Methods: Cortical mRNA profiles of adult HuD KO (Elavl4 -/-) mice and Control mice were generated by RNA sequencing, in triplicate, using Illumina NovaSeq 6000 platform. The quality of raw RNA-sequencing reads was evaluated using FastQC software (version 0.11.5) and adapters were removed using the Cutadapt (version 1.15) and Trimmomatic (version 0.38) software. Alternative splicing was evaluated using rMATS software (version 4.0.2) and BAM files were converted to BedGraph before examining alternative polyadenylation using DaPars software (version 0.9.1) Methods (cont.): RNA-seq data was aligned to the M musculus genome (UCSC browser, mm10) using STAR (version 2.7.3a), and MultiQC (version 1.8) was used to perform a final quality check on STAR alignment files. If alignments were found to be the same read length and have >80% reads mapped to a unique location, the data was considered good quality and alternative splicing and polyadenylation analyses were performed. Sequence reads per sample were aligned to the mouse genome (build mm10). Results: HuD KO affected alternative splicing of 310 genes, including 17 validated HuD targets such as Cbx3, Cspp1, Snap25 and Gria2. In addition, deletion of HuD affected polyadenylation of 53 genes, with the majority of significantly altered mRNAs shifting towards usage of the proximal polyadenylation signal (PAS), resulting in shorter 3’ untranslated regions (3’ UTRs). Conclusions: HuD KO had a greater effect on alternative splicing than polyadenylation, with many of the affected genes implicated in several neuronal functions and neuropsychiatric disorders.

2021-03-17 | GSE169023 | GEO

Transcriptome-wide analysis of HuD (ELAVL4) RNA interactome and post-transcriptional regulation in a motor neuron cell line

Project description:The neuronal ELAV-like RNA-binding protein HuD (ELAVL4) plays important roles in multiple post-transcriptional regulatory processes, including RNA stability, transport and translation. Besides its functional role in neuronal plasticity, HuD has been implicated in peripheral axon injury recovery and motor neuronal function. The characterization of HuD specific interactions has always been a challenging task due to the high similarity of sequence and structure with the other members of the ELAVL family, and the lack of specific antibodies. To selectively identify in vivo HuD binding sites, we adapted the CRAC protocol (cross-linking and analysis of cDNAs), originally developed for yeast, to be used with mouse motor neuron NSC-34 cells engineered with inducible tagged HuD. In parallel, to characterize the role of HuD in post-transcriptional regulation, we also profiled the transcriptome (total RNA, RNA-Seq), the translatome (polysomal RNA, POL-Seq) and the alternative polyadenilation (APA, 3’end mRNA sequencing) of HuD induced and control NSC-34 cells. Keywords: HuD, Elavl4, Y3, Rny3, CRAC, RNA interactome, RNA binding, NSC-34, transcriptome profiling, translatome profiling, RNA-Seq, POL-Seq, motor neuron

2018-07-13 | GSE115490 | GEO

Expression data from P0 forebrain of wild-type and Elavl3/Elavl4 double knockout mice.

Project description:Neuronal Elavl-like (nElavl) RNA binding proteins have three paralogs (Elavl2, Elavl3 and Elavl4) in the mouse genome. This family of RNABPs have been implicated in a variety of post-transcriptional RNA processing mechanisms, including regulation of mRNA stability, alternative splicing, and translational regulation. In this study, using mouse exon arrays, we identify significant differences (p<0.01) in 119 transcripts between wild-type and Elavl3/Elavl4 double knockout forebrain tissue at postnatal day 0. A total of 10 samples were analyzed. These samples consisted of 5 littermate pairs of wild-type and Elavl3/Elavl4 double knockout mice.

2013-01-05 | E-GEOD-43287 | biostudies-arrayexpress

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

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

Expression data from P0 forebrain of wild-type and Elavl3/Elavl4 double knockout mice.

2013-01-05 | GSE43287 | GEO

RNA Sequencing analyses of control and HuD KO (Elavl4 null) mouse cortical transcriptomes

Project description:RNA Sequencing analyses of control and HuD KO (Elavl4 null) mouse cortical transcriptomes

| PRJNA714916 | ENA

Emerging Roles for the RNA-Binding Protein HuD (ELAVL4) in Nervous System Diseases.

Project description:The main goal of this review is to provide an updated overview of the involvement of the RNA-binding protein (RBP) HuD, encoded by the ELAVL4 gene, in nervous system development, maintenance, and function, and its emerging role in nervous system diseases. A particular focus is on recent studies reporting altered HuD levels, or activity, in disease models and patients. Substantial evidence suggests HuD involvement in Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Interestingly, while possible disease-causing mutations in the ELAVL4 gene remain elusive, a common theme in these diseases seems to be the altered regulation of HuD at multiple steps, including post-transcriptional and post-translational levels. In turn, the changed activity of HuD can have profound implications for its target transcripts, which are overly stabilized in case of HuD gain of function (as proposed in PD and ALS) or reduced in case of decreased HuD binding (as suggested by some studies in AD). Moreover, the recent discovery that HuD is a component of pathological cytoplasmic inclusion in both familial and sporadic ALS patients might help uncover the common molecular mechanisms underlying such complex diseases. We believe that deepening our understanding of the involvement of HuD in neurodegeneration could help developing new diagnostic and therapeutic tools.

| S-EPMC9736382 | biostudies-literature