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Shifts in Ribosome Engagement Impact Key Gene Sets in Neurodevelopment and Rett Syndrome Neurons

ABSTRACT: Regulation of translationduring early human development is poorly understood anditsdysregulation is associated with disease. To discover shifts in mRNA ribosomal engagement (RE) that occur during human neurodevelopment and disease, we used parallel TRAPSeq and RNASeq on control and Rett syndrome (RTT) human induced pluripotent stem cells,neural progenitor cells and cortical neurons. We found 30% of transcribed genes were translationally regulatedincluding key gene sets (neurodevelopment, transcription and translation factors, glycolysis). Neurons more efficiently translated global mRNAs,had longer 3`UTRs and RE correlated with RNA-binding protein motif composition.In contrast, RTT neurons had reduced global translation,compromised mTOR signalingand 2100 genes were translationally dysregulated. NEDD4L E3-ubiquitin ligasewas most translationally impaired, and its protein targets accumulatedin RTT neurons. Our findings reveal a dynamic translatome in neurodevelopment, show that MECP2 regulatestranslationandubiquitin enzymes in neurons, and provide novel insight into altered proteostasis that may have therapeutic implications for RTT.

OTHER RELATED OMICS DATASETS IN: PXD011961

ORGANISM(S): Homo sapiens

PROVIDER: GSE123753 | GEO | 2020/04/28

REPOSITORIES: GEO

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Shifts in Ribosome Engagement Impact Key Gene Sets in Neurodevelopment and Rett Syndrome Neurons

Project description:Translation of many transcripts is highly regulated in the developing brain, and disturbance of translational regulation machinery contributes to neurodevelopmental disorders. In neural progenitor cells, for example, several critical pro-differentiation genes are transcribed, but their translation is repressed to allow rapid translation when appropriate signals to differentiate are received. This layer of translational regulation makes it challenging to directly correlate RNA and protein levels in stem cells and neurons. During early neural development, translation is regulated by several pathways that can impact neuron fate and function. The mTOR-mediated signaling pathway plays a crucial role in the induction of neuron differentiation, axon and dendrite development, and gliogenesis, while being key in the maintenance of pluripotent and neural stem cells {Wang:2013hg}{Agrawal:2014ek}{Ka:2014fq}. Dysregulation of the translation repressor eIF4E-binding protein 2 (4EBP2), a downstream target of mTORC1, leads to an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviors {Gkogkas:2013fh}. The Fragile X Mental Retardation Protein (FMRP), which is encoded by the FMR1 gene {Verkerk:1991hu}, is an RNA binding protein (RBP) that regulates translation through multiple mechanisms {Richter:2015ii}. Loss of expression of FMR1 causes Fragile X Syndrome (FXS), the most common inherited intellectual disability as well as the most prevalent single-gene cause of autism spectrum disorder (ASD). FMRP typically functions as a translational repressor {Li:2001ds} and some studies suggest that FXS results from an inability of neurons to achieve regulated local translation, particularly in response to stimuli {Richter:2015ii}. This suggests important roles for control of translation in stem cells and neurons, and an association with significant risk for neurodevelopmental disorders.

2020-05-07 | PXD011961 | Pride

Shifts in Ribosome Engagement Impact Key Gene Sets in Neurodevelopment and Rett Syndrome Neurons

Project description:Shifts in Ribosome Engagement Impact Key Gene Sets in Neurodevelopment and Rett Syndrome Neurons

| PRJNA509687 | ENA

5-hydroxymethylcytosine-mediated epigenetic dynamics during neurodevelopment and aging

Project description:This SuperSeries is composed of the following subset Series: GSE32050: 5-hydroxymethylcytosine-mediated epigenetic dynamics during neurodevelopment and aging [5hmC Capture and Seq] GSE32187: 5-hydroxymethylcytosine-mediated epigenetic dynamics during neurodevelopment and aging [mRNA profiling] Refer to individual Series

2011-10-29 | E-GEOD-32188 | biostudies-arrayexpress

The Circular RNA Edis Regulates Neurodevelopment and Innate Immunity

Project description:Circular RNAs (circRNAs) are widely expressed in eukaryotes. However, only a subset have been functionally characterized. We identify and validate a collection of circRNAs in Drosophila, and show that depletion of the brain-enriched circRNA Edis causes hyperactivation of antibacterial innate immunity both in cultured cells and in vivo. Notably, Edis depleted flies display heightened resistance to bacterial infection and enhanced pathogen clearance. Conversely, ectopic Edis expression blocks innate immunity signaling. In addition, inactivation of Edis in vivo leads to impaired locomotive activity and shortened lifespan. Remarkably, these phenotypes can be recapitulated with neuron-specific depletion of Edis, accompanied by defective neurodevelopment. Importantly, restoration of Edis expression suppresses both innate immunity and neurodevelopment phenotypes elicited by Edis depletion. We provide evidence that Edis encodes a functional protein that associates with and compromises the processing of the immune transcription factor Relish. Consistent with these observations, inactivation of Relish suppresses the innate immunity hyperactivation phenotype in the fly brain and rescues the neurodevelopment defects in Edis knockdown neurons. Thus, our study establishes the circRNA Edis as a key regulator of neurodevelopment and innate immunity.

2022-10-04 | GSE188484 | GEO

Loss of GTF2I promotes neuronal apoptosis and synaptic reduction in human cellular models of neurodevelopment

Project description:Individuals with Williams syndrome (WS), a multisystemic neurodevelopmental disorder, characteristically portray a hypersocial phenotype. WS is caused by the hemizygous loss of 26-28 genes at chromosomal locus 7q11.23, one of which is GTF2I. Copy number variations and mutations in GTF2I are associated with altered sociality and have been proposed to underlie the hypersocial expression of WS. However, the contribution of GTF2I to human neurodevelopment remains poorly understood. Here, human cellular models of neurodevelopment, including neural progenitors, neurons, and three-dimensional cortical organoids, were differentiated from CRISPR-Ca9-edited GTF2I-knockout (GTF2I-KO) pluripotent stem cells (hiPSCs) to investigate the role of GTF2I in human neurodevelopment. Compared to controls, GTF2I-KO progenitors exhibited an increased proliferation rate and an altered cell cycle profile. Cortical organoids and neurons demonstrated increased cell death and synaptic dysregulation, including synaptic structural dysfunction and decreased electrophysiological activity on a multi-electrode array. Overall, our findings suggest that changes in synaptic circuit integrity may be a prominent mediator of the link between alterations in GTF2I and variation in the phenotypic expression of human sociality.

2024-01-11 | GSE252761 | GEO

Transcriptomic analysis in Suv39h2-deficient brain during early neurodevelopment

Project description:To examine the molecular phenotype of Suv39h2-deficits during early neurodevelopment, transcriptome analysis in the E11.5 brain of Suv39h2-deficient mouse and wild-type littermates were performed. The Suv39h2 mutation was made using CRISPR/Cas9n-mediated genome editing

2023-12-30 | E-MTAB-10528 | biostudies-arrayexpress

Identification of TIA1 mRNA targets during human neuronal development

Project description:Background: Neuronal development is a tightly controlled process involving multi-layered regulatory mechanisms. While transcriptional pathways regulating neurodevelopment are well characterized, post-transcriptional programs are still poorly understood. TIA1 is an RNA-binding protein that can regulate splicing, stability, or translation of target mRNAs, and has been shown to play critical roles in neurodevelopment. However, the identity of mRNAs regulated by TIA1 during neurodevelopment is still unknown. Methods and Results: To identify the mRNAs targeted by TIA1 during the first stages of human neurodevelopment, we performed RNA immunoprecipitation-sequencing (RIP-seq) on human embryonic stem cells (hESCs) and derived neural progenitor cells (NPCs), and cortical neurons. While there was no change in TIA1 protein levels, the number of TIA1 targeted mRNAs decreased from pluripotent cells to neurons. We identified 2400, 845, and 330 TIA1 mRNA targets in hESCs, NPC, and neurons, respectively. The vast majority of mRNA targets in hESC were genes associated with neurodevelopment and included autism spectrum disorder-risk genes that were not bound in neurons. Additionally, we found that most TIA1 mRNA targets have reduced ribosomal engagement levels. Conclusion: Our results reveal TIA1 mRNA targets in hESCs and during human neurodevelopment, indicate that translation repression is a key process targeted by TIA1 binding and implicate TIA1 function in neuronal differentiation.

2021-06-01 | GSE166306 | GEO

5-hydroxymethylcytosine-mediated epigenetic dynamics during neurodevelopment and aging [mRNA profiling]

Project description:DNA methylation dynamics influence brain function and are altered in neurological disorders. 5-hydroxymethylcytosine (5-hmC), a DNA base derived from 5-methylcytosine (5mC) accounts for ~40% of modified cytosine in brain, and has been implicated in DNA methylation-related plasticity. Here we map 5-hmC genome-wide across three ages in mouse hippocampus and cerebellum, allowing assessment of its stability and dynamic regulation during postnatal neurodevelopment through adulthood. We find developmentally programmed acquisition of 5-hmC in neuronal cells. Epigenomic localization of 5-hmC-regulated regions reveals stable and dynamically modified loci during neurodevelopment and aging. By profiling 5-hmC in human cerebellum we establish conserved genomic features of 5-hmC. Finally, we implicate 5-hmC in neurodevelopmental disease by finding that its levels are inversely correlated with methyl-CpG-binding protein 2 (Mecp2) dosage, a protein encoded by a gene in which mutations cause Rett Syndrome. These data point toward critical roles for 5-hmC-mediated epigenetic modification in neurodevelopment and diseases. Gene expression data derived from P7 and 6wk mouse cerebellum used for determining expression outcomes associated with dynamic alterations in 5-hydroxymethylcytosine

2011-10-29 | E-GEOD-32187 | biostudies-arrayexpress

5-hydroxymethylcytosine-mediated epigenetic dynamics during neurodevelopment and aging [5hmC Capture and Seq]

Project description:DNA methylation dynamics influence brain function and are altered in neurological disorders. 5-hydroxymethylcytosine (5-hmC), a DNA base derived from 5-methylcytosine (5mC) accounts for ~40% of modified cytosine in brain, and has been implicated in DNA methylation-related plasticity. Here we map 5-hmC genome-wide across three ages in mouse hippocampus and cerebellum, allowing assessment of its stability and dynamic regulation during postnatal neurodevelopment through adulthood. We find developmentally programmed acquisition of 5-hmC in neuronal cells. Epigenomic localization of 5-hmC-regulated regions reveals stable and dynamically modified loci during neurodevelopment and aging. By profiling 5-hmC in human cerebellum we establish conserved genomic features of 5-hmC. Finally, we implicate 5-hmC in neurodevelopmental disease by finding that its levels are inversely correlated with methyl-CpG-binding protein 2 (Mecp2) dosage, a protein encoded by a gene in which mutations cause Rett Syndrome. These data point toward critical roles for 5-hmC-mediated epigenetic modification in neurodevelopment and diseases. Here we map 5-hmC genome-wide across three ages in mouse hippocampus and cerebellum, allowing assessment of its stability and dynamic regulation during postnatal neurodevelopment through adulthood. Profiling of 5-hmC in human cerebellum we establish conserved genomic features of 5-hmC. Finally, we implicate 5-hmC in neurodevelopmental disease by profiling 5-hmC in mouse cerebellum lacking MeCP2, a protein encoded by a gene in which mutations cause Rett Syndrome.

2011-10-30 | E-GEOD-32050 | biostudies-arrayexpress

KDM5C safeguards the appropriate timing of early neurodevelopment

Project description:We generated human induced pluripotent cells from intellectual disability patients carrying the c.2T>C mutation in KDM5C (Called “Mutant”). We generated a paired, isogenic human iPS cell line (called “Corrected”) using CRISPR/Cas9 and PiggyBac gene-editing technologies and conducted neuronal differentiation based on “Yichen Shi et al. Nat. Protoc. 7, 1836–1846 (2012)” to define differences in gene expression between the Mutant and Corrected during neurodevelopment.

2023-10-13 | E-MTAB-7551 | biostudies-arrayexpress

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