Investigation of Chimeric Transcripts Derived from LINE-1 and Alu Retrotransposons in Cerebellar Tissues of Individuals with Autism Spectrum Disorder (ASD)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1120182 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29287300_1.fastq.gz | Fastqsanger.gz | |||
| SRR29287300_2.fastq.gz | Fastqsanger.gz | |||
| SRR29287301_1.fastq.gz | Fastqsanger.gz | |||
| SRR29287301_2.fastq.gz | Fastqsanger.gz | |||
| SRR29287302_1.fastq.gz | Fastqsanger.gz |
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Project description:LINE-1 and Alu retrotransposons are components of the human genome and have been implicated in many human diseases. These elements can influence human transcriptome plasticity in various mechanisms. Chimeric transcripts derived from LINE-1 and Alu can also impact the human transcriptome, such as exonization and post-transcriptional modification. However, its specific role in ASD neuropathology remains unclear, particularly in the cerebellum tissues. We performed RNA-sequencing of post-mortem cerebellum tissues from ASD and unaffected individuals for transposable elements profiling and chimeric transcript identification. The majority of free transcripts of transposable elements were not changed in the cerebellum tissues of ASD compared with unaffected individuals. Nevertheless, we observed that chimeric transcripts derived from LINE-1 and Alu were embedded in the transcripts of differentially expressed genes in the cerebellum of ASD, and these genes were related to developments and abnormalities of the cerebellum. In addition, the expression levels of these genes were correlated with the significantly decreased thickness of the molecular layer in the cerebellum of ASD. We also found that global methylation and expression of LINE-1 and Alu elements were not changed in ASD, but observed in the ASD sub-phenotypes. Our findings showed associations between transposable elements and cerebellar abnormalities in ASD, particularly in distinct phenotypic subgroups. Further investigations using appropriate models are warranted to elucidate the structural and functional implications of LINE-1 and Alu elements in ASD neuropathology.
2024-08-22 | GSE269105 | GEO
Project description:Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. Individuals with ASTN2 mutations exhibit neurodevelopmental disorders, including autism spectrum disorder (ASD), ADHD, learning difficulties and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study the role of ASTN2 in cerebellar circuit function, we generated global and PC-specific conditional Astn2 knockout (KO and cKO, respectively) mouse lines. Astn2 KO mice exhibited strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity, and repetitive behaviors, altered behavior in the three-chamber test, and impaired cerebellar-dependent eyeblink conditioning. Hyperactivity and repetitive behaviors were also prominent in Astn2 cKO animals but they did not show altered behavior in the three-chamber test. By Golgi staining, Astn2 KO PCs had region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of Astn2 KO cerebellum revealed a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrated a significant increase in Bergmann glia volume in the molecular layer of Astn2 KO animals. Electrophysiological experiments indicated a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs), as well as increased amplitudes of both spontaneous EPSCs and inhibitory postsynaptic currents (IPSCs) in the Astn2 KO animals, suggesting that pre- and postsynaptic components of synaptic transmission were altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.
2024-07-30 | PXD052868 | Pride
Project description:LINE-1 and Alu retrotransposons are components of the human genome and have been implicated in many human diseases. These elements can influence human transcriptome plasticity in various mechanisms. Chimeric transcripts derived from LINE-1 and Alu can also impact the human transcriptome, such as exonization and post-transcriptional modification. However, its specific role in ASD neuropathology remains unclear, particularly in the cerebellum tissues. We performed RNA-sequencing of post-mortem cerebellum tissues from ASD and unaffected individuals for transposable elements profiling and chimeric transcript identification. The majority of free transcripts of transposable elements were not changed in the cerebellum tissues of ASD compared with unaffected individuals. Nevertheless, we observed that chimeric transcripts derived from LINE-1 and Alu were embedded in the transcripts of differentially expressed genes in the cerebellum of ASD, and these genes were related to developments and abnormalities of the cerebellum. In addition, the expression levels of these genes were correlated with the significantly decreased thickness of the molecular layer in the cerebellum of ASD. We also found that global methylation and expression of LINE-1 and Alu elements were not changed in ASD, but observed in the ASD sub-phenotypes. Our findings showed associations between transposable elements and cerebellar abnormalities in ASD, particularly in distinct phenotypic subgroups. Further investigations using appropriate models are warranted to elucidate the structural and functional implications of LINE-1 and Alu elements in ASD neuropathology.
| S-EPMC11412982 | biostudies-literature
Project description:Astrotactin 2 (ASTN2) is a transmembrane, neuronal protein that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. We recently reported a family with a paternally inherited intragenic ASTN2 duplication, with a range of neurodevelopmental disorders, including autism spectrum disorder (ASD), learning difficulties and speech and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study ASTN2 role in cerebellar circuit function, we generated global and Purkinje cell-specific conditional Astn2 knockout (KO and cKO, respectively) mouse lines. Astn2 KO mice exhibit strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization (USV) calls, increased hyperactivity and repetitive behaviors, altered social behaviors, and impaired cerebellar-dependent eyeblink conditioning. Increased hyperactivity and repetitive behaviors were also prominent in Astn2 cKO animals. By Golgi staining, Astn2 KO PCs have region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of Astn2 KO cerebellum reveals a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrates a large increase in Bergmann glia volume in the molecular layer of Astn2 KO animals. Electrophysiological experiments indicate a reduced frequency of spontaneous EPSCs, as well as increased amplitudes of both spontaneous EPSCs and IPSCs in the Astn2 KO animals, suggesting that pre- and post-synaptic components of synaptic transmission are altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.
2024-03-07 | GSE254224 | GEO
Project description:Interleukin-17 (IL-17) is a pleiotropic cytokine produced mainly by peripheral Th17 cells. Yet, brain functions of IL-17 derived from central nervous cells remain poorly understood. Here, we find an aberrant IL-17A signaling in the cerebellum of Fmr1-KO mice, a well-established genetic model for autism spectrum disorder (ASD). Cerebellar IL-17A, derived exclusively from microglia, is essential for the regulation of social behaviors by maintaining neuronal excitability and selectively suppressing inhibitory neurotransmission of Purkinje cells (PCs) in the cerebellar Crus I, a brain region critically involved in social cognition. Specific downregulation of IL-17 receptor-mediated signaling in cerebellar PCs recapitulates ASD-like social deficits and repetitive behaviors. Notably, both direct administration of IL-17A and induction of IL-17A release from cerebellar microglia by poly(I:C) effectively restore PC excitability and ameliorate ASD-like symptoms. The findings uncover an indispensable role of microglia-derived IL-17A for cerebellar social processing and suggest potential therapeutic strategies targeting IL-17A signaling for ASD.
2026-02-03 | GSE287731 | GEO
Project description:Interleukin-17 (IL-17) is a pleiotropic cytokine produced mainly by peripheral Th17 cells. Yet, brain functions of IL-17 derived from central nervous cells remain poorly understood. Here, we find an aberrant IL-17A signaling in the cerebellum of Fmr1-KO mice, a well-established genetic model for autism spectrum disorder (ASD). Cerebellar IL-17A, derived exclusively from microglia, is essential for the regulation of social behaviors by maintaining neuronal excitability and selectively suppressing inhibitory neurotransmission of Purkinje cells (PCs) in the cerebellar Crus I, a brain region critically involved in social cognition. Specific downregulation of IL-17 receptor-mediated signaling in cerebellar PCs recapitulates ASD-like social deficits and repetitive behaviors. Notably, both direct administration of IL-17A and induction of IL-17A release from cerebellar microglia by poly(I:C) effectively restore PC excitability and ameliorate ASD-like symptoms. The findings uncover an indispensable role of microglia-derived IL-17A for cerebellar social processing and suggest potential therapeutic strategies targeting IL-17A signaling for ASD.
2026-02-03 | GSE287705 | GEO
Project description:Background: Transcriptome analysis has been used in autism spectrum disorder (ASD) to unravel common pathogenic pathways based on the assumption that distinct rare genetic variants or epigenetic modifications affect common biological pathways dysregulated in ASD. To unravel recurrent ASD-related neuropathological mechanisms, we took advantage of the En2-/- mouse model and performed transcriptome profiling on cerebellar and hippocampal adult tissues. Methods: En2-/- and WT cerebellar and hippocampal tissue from littermate mice were assessed for differential gene expression using microarray hybridization followed by RankProd analysis. To identify functional categories overrepresented in the differentially expressed genes we used the BIOBASE ExPlain system and mouse phenotype ontology database. Furthermore, we performed direct enrichment analysis of ASD associated genes from the SFARI repository in our differentially expressed genes. Results: We found 842 differentially expressed genes in En2-/- cerebellum and 862 in the En2-/- hippocampus. Our functional analysis revealed that the molecular signature of En2-/- cerebellum and hippocampus shares convergent pathological pathways with ASD, including abnormal synaptic transmission, altered developmental processes and increased immune response. Furthermore, when directly compared to the repository of the SFARI database, our differentially expressed genes show enrichment of ASD-associated genes significantly higher than previously reported. Among the differentially expressed genes 20 were validated by quantitative PCR. Conclusions: Our results indicate the En2-/- mouse model of ASD as an appropriate tool to investigate molecular alterations related to ASD. En2-/- and WT cerebellar and hippocampal tissue from 3 littermates mice for each genotype was hybridized on three replicates microarrays.
2013-12-23 | E-GEOD-51612 | biostudies-arrayexpress
Project description:Mice lacking Astn2 have ASD-like behaviors and altered cerebellar circuit properties
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Project description:Our work sheds light on the metabolism of RNA transcripts derived from genomic Alu repeats. Since it is unclear whether Alu elements are transcribed mainly by RNA polymerase II or III, we conducted a transcription shutoff experiment and metabolic RNA labeling. We find that Alu transcripts are as stable as mRNAs and originate in part from RNA polymerase II. Furthermore, we use the de Bruijn graph of all Alu sequences to discover sequence features that match transcription factor binding motifs.
2022-04-01 | GSE185485 | GEO
Project description:Mutations in the gene encoding the chromatin remodeler CHD8 are a highly penetrant risk factor for autism spectrum disorder (ASD). Although cerebellar abnormalities have been involved in ASD pathogenesis, the underlying mechanisms of CHD8 in the regulation of cerebellar function has remained unknown, however. Here we show that the cerebellar granule neurons–specific deletion of Chd8 manifests reduced proliferation and differentiation of granule neuron progenitors, leading to cerebellar hypoplasia and motor coordination defects in mice. CHD8 was found to regulate the expression of neuronal genes and to be required for maturation of cerebellar granule neurons. Furthermore, we found that CHD8 is preferentially bound to promoter regions and is necessary for modulation of local chromatin accessibilities at promoter regions of active gene. Our results thus uncover a critical role for CHD8 in cerebellar development and have important implications for understanding the cerebellar contributions to ASD pathogenesis.
2021-04-16 | GSE146885 | GEO