Shifts in Ribosome Engagement Impact Key Gene Sets in Neurodevelopment and Rett Syndrome Neurons
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA509687 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description: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.
2020-04-28 | GSE123753 | GEO
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
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
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
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.
2011-10-30 | GSE32187 | GEO
Project description:The change in abundance of individual mRNAs as cells differentiate through neurodevelopmental stages is generally attributed to transcription level alterations while the potential contribution of mRNA half-life is commonly overlooked. While some genes are regulated solely by transcription, others may be regulated by mRNA half-life only, or genes with changed transcription rates could be buffered by compensating half-life decreases or even boosted by amplifying half-life increases. In addition, during neurodevelopment there is widespread 3ʹUTR lengthening that could be shaped by differential shifts in the stability of transcript isoforms. Here we measure transcription rate and mRNA half-life changes during induced Pluripotent Stem Cell-derived neuronal development using RATE-seq at the resolution of gene isoforms. We found that during transitions to progenitor and neuron stages, transcript buffering occurs in up to half of all genes. Half-life only changes are observed in as many genes as transcription rate only changes, and almost 10% of genes exhibit transcript boosting. Global mRNA half-life decreases two-fold in neurons relative to iPSCs. The observed mRNA destabilization differentially affects gene isoforms and contributes to 3ʹUTR lengthening. Small RNA sequencing further captured an increase in microRNA copy number per cell. We propose that mRNA destabilization and 3ʹUTR lengthening are driven in part by an increase in microRNA load. Our findings identify mRNA stability mechanisms in human neurodevelopment that regulate gene and isoform level abundance and provide a precedent for similar post-transcriptional regulatory events as other tissues develop.
2023-09-01 | GSE212990 | GEO
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.
2011-10-30 | GSE32050 | GEO
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
Project description:Transcriptome analysis of postmortem brain samples frrom frontal and temporal cortex of Rett Syndrome cases and matched controls. These data identify genes differentially expressed in postmortem brain tissue from Rett Syndrome cases. Total RNA was extracted from 100mg of postmortem brain tissue.
2015-11-24 | E-GEOD-75303 | biostudies-arrayexpress
Project description:Transcriptome analysis of postmortem brain samples frrom frontal and temporal cortex of Rett Syndrome cases and matched controls. These data identify genes differentially expressed in postmortem brain tissue from Rett Syndrome cases.
2015-11-24 | GSE75303 | GEO