FMRP targets in human neurons
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA914736 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22851343.fastq.gz | Fastqsanger.gz | |||
| SRR22851344.fastq.gz | Fastqsanger.gz | |||
| SRR22851345.fastq.gz | Fastqsanger.gz | |||
| SRR22851346.fastq.gz | Fastqsanger.gz | |||
| SRR22851347.fastq.gz | Fastqsanger.gz |
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Project description:Loss of the neuronal RNA binding protein FMRP causes Fragile X Syndrome (FXS), the most common cause of inherited intellectual disability, yet it is unknown which brain regions and cell types within them contribute to disease pathophysiology. We used conditional tagging of FMRP and CLIP (cTag FMRP CLIP) to examine FMRP targets specifically in CA1 hippocampal neurons, a critical cell type for learning and memory known to have altered synaptic function in FXS. Integrating this data with analysis of ribosome-bound transcripts from the same neuronal population revealed CA1-enriched binding of autism-relevant mRNAs, and unexpected CA1-specific regulation of transcripts encoding circadian proteins.
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Project description:In this study, we sought to identify the mRNAs associated to FMRP protein in mouse cortical neuron using a cross linking immunoprecipitation and microarray (CLIP-microarray). The mRNAs crosslinked at 254 nm to FMRP in mouse cortical neurons cultured 8 days in vitro (8 DIV) were immunoprecipitated with H120 anti-FMRP (Santa Cruz) and reverse transcribed to labeled cDNAs with Ovation Pico WTA system V2 (Nugen) and hybridized on Mouse Gene 1.0ST (Affymetrix) We analyzed total RNA (Input) and FMRP-CLIPed RNA (Clip) from 10 primary cortical neuron mouse cultures (5 Wt Input, 5 FMR1-KO Input, 5 Wt Clip, 5 FMR1-KO Clip). Array data was processed by Affymetrix Exon Array Computational Tool. No technical replicates were performed.
2016-06-01 | E-GEOD-51649 | biostudies-arrayexpress
Project description:We report cell-type and compartment-specific TRAP-seq, RNAseq, FMRP-CLIP, and PAPERCLIP from CA1 hippocampal neurons. We use TRAP-seq and PAPERCLIP data to precisely define the dendritic transcriptome, including mRNAs that harbor APA and AS events that are differentially localized. Further, we use FMRP-CLIP in order to define mRNAs that undergo compartment-specific regulation by FMRP.
2022-05-11 | GSE180412 | GEO
Project description:In this study, we sought to identify the mRNAs associated to FMRP protein in mouse cortical neuron using a cross linking immunoprecipitation and microarray (CLIP-microarray). The mRNAs crosslinked at 254 nm to FMRP in mouse cortical neurons cultured 8 days in vitro (8 DIV) were immunoprecipitated with H120 anti-FMRP (Santa Cruz) and reverse transcribed to labeled cDNAs with Ovation Pico WTA system V2 (Nugen) and hybridized on Mouse Gene 1.0ST (Affymetrix)
2016-06-01 | GSE51649 | GEO
Project description:Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and a leading genetic cause of autism. FXS is caused by the loss of functional fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein forming a messenger ribonucleoprotein complex with polyribosomes in the regulation of protein synthesis at synapses. Three-dimensional (3D) aggregate culture of human-induced pluripotent stem cells (iPSCs) has evolved from embryoid body cultures, quite faithfully following human organogenesis, and provides a new platform to investigate human brain development in a dish, otherwise inaccessible to experimentation. To determine whether the loss of FMRP could alter the development of human brain organoids, we have generated forebrain organoids from three FXS male patients and three healthy male controls. We observed reduced proliferation of neural progenitor cells and premature neural differentiation as well as perturbed cell cycle progression in FXS forebrain organoids. There is also a deficit in the production of GABAergic neurons as well as an altered balance between the number of excitatory and inhibitory neurons in FXS organoids. Interestingly these deficits were not observed with FXS mouse model. To compare the differential gene expression caused by the loss of FMRP between human and mouse, we then performed RNA-seq to identify the differentially expressed genes using both mouse embryonic brain cortex and human forebrain organoids at the comparable developmental stages. We detected very few genes differentially expressed in the absence of Fmrp in mouse. However, we identified 200 genes downregulated and 126 genes up-regulated in human FXS organoids, indicating human-specific impact caused by the loss of FMRP. Our bulk RNA-seq analyses revealed a more pervasive gene expression alteration in human organoids. Thus, it is plausible to speculate that there could be important human-specific genes that might be related with FXS pathogenesis. To test this idea, we used human forebrain organoids and the mouse embryonic brains in parallel to perform enhanced crosslinking and FMRP immunoprecipitation followed by high-throughput sequencing and bioinformatics analysis (CLIP-seq). Our analyses identified more than 3,700 mRNA bound by FMRP in human organoids. Of the 3,700 mRNAs, ~1,600 overlapped with mouse mRNAs. Further, ~80% of the identified mouse mRNA species overlap with previously published results in mouse. To better understand the developmental, cellular and molecular changes and to gain insight beyond bulk gene expression analysis in forebrain organoids from FXS patients compared to control, we next performed single cell RNA-seq (scRNA-seq) to characterize distinct cell populations, specific cell types and cell states. We found that the population of specific neuron type were changed upon the loss of FMRP. Next, investigated if there were developmental differences in the transitioning from the early, primitive state to one of the more committed end states between control and FXS organoids, with many cells distributed along a “trajectory” between them. we found several bifurcation points of FXS cells from the general trajectory, and the cells of these subpopulations with altered neuronal states are strongly enriched for FXS. These results together suggest that the loss of FMRP could cause neurodevelopmental deficits specifically in human, and fragile X organoids could provide a unique platform to study the molecular pathogenesis of FXS and identify human-specific druggable targets for FXS and autism in general.
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Project description:FMRP cTag CLIP from mouse CA1 pyramidal neurons
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Project description:Neuronal diversity and function are intricately linked to the dynamic regulation of RNA metabolism, including splicing, localization, and translation. Electrophysiologic studies of synaptic plasticity, models for learning and memory, are disrupted in Fragile X Syndrome (FXS). FXS is characterized by the loss of FMRP, an RNA-binding protein (RBP) known to bind and suppress translation of specific neuronal RNAs. Since molecular studies have demonstrated that synaptic plasticity in CA1 excitatory hippocampal neurons is protein-synthesis dependent, together these observations have suggested a potential role for FMRP in synaptic plasticity in FXS. To explore this model, we developed a new experimental platform, Opto-CLIP, to integrate optogenetics with cell-type specific FMRP CLIP and RiboTag in CA1 hippocampal neurons, allowing investigation of FMRP- regulated dynamics after neuronal activation. We tracked changes in FMRP binding and ribosome- associated RNA profiles 30 minutes after neuronal activation. Our findings reveal a significant reduction in FMRP-RNA binding to transcripts encoding nuclear proteins, suggesting FMRP translational inhibition may be de-repressed to allow rapid translational responses required for neuronal homeostasis. In contrast, FMRP binding to transcripts encoding synaptic targets were generally stable after activation, but all categories of targets demonstrated variability in FMRP translational control. Opto-CLIP revealed differential regulation of subsets of transcripts within CA1 neurons rapidly after depolarization, and offers promise as a generally useful platform to uncover mechanisms of RBP-mediated RNA regulation in the context of synaptic plasticity.
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