Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Common schizophrenia risk variants are implicated in the function of glutamatergic neurons

ABSTRACT: The epigenome of human brain cells encompasses key information in understanding brain function in both healthy and diseased states. To further explore this, we used ATAC-seq to profile chromatin structure in four distinct populations of cells (glutamatergic neurons, GABAergic neurons, oligodendrocytes, and microglia/astrocytes), from three different regions of the brain. Chromatin accessibility was found to vary vastly by cell type and, more moderately, by brain region, with glutamatergic neurons showing the greatest regional variability. Transcription factor footprinting pointed to cell-specific transcriptional regulators and inferred cell-specific regulation of protein coding genes, long intergenic noncoding RNAs, and microRNAs. In vivo transgenic mouse experiments validated the cell type specificity of a number of human-derived regulatory sequences. Open chromatin regions in glutamatergic neurons were enriched for neuropsychiatric risk variants, particularly those associated with schizophrenia. Combining differential chromatin accessibility analysis using ATAC-seq data from bulk tissue increased our statistical power to confirm glutamatergic neurons as the cell type most affected in schizophrenia. Jointly, these findings illustrate the utility of studying the cell type specific epigenome in complex tissues such as the human brain and implicate an association among chromatin accessibility in glutamatergic neurons and genetic risk for schizophrenia.

ORGANISM(S): Homo sapiens

PROVIDER: GSE143666 | GEO | 2020/08/20

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

ATAC-seq of mESCs differentiation into neurons

Project description:Mouse WT129 ESCs were differentiated into glutamatergic neurons and samples were collected at days 0 (mESCs), 4 (embryoid bodies), 8 (neuronal precursors) and 12 (neurons). ATAC-seq experiment in 4 biological replicates was performed at 4 indicated above time points to profile chromatin structure changes during differentiation.

2020-05-20 | E-MTAB-8194 | biostudies-arrayexpress

An Atlas of Chromatin Accessibility in the Adult Human Brain

Project description:The majority of common genetic risk variants associated with neuropsychiatric disease are non-coding and are thought to exert their effects by disrupting the function of cis regulatory elements (CREs), including promoters and enhancers. Within each cell, chromatin is arranged in specific patterns to expose the repertoire of CREs required for optimal spatiotemporal regulation of gene expression. To further our understanding of the complex mechanisms that modulate transcription in the brain, we utilized frozen postmortem samples to generate the largest human brain and cell type-specific open chromatin dataset to date. Using the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq), we created maps of chromatin accessibility in 2 cell types (neurons and non-neurons) across 14 distinct brain regions of 5 individuals. Chromatin structure varies markedly by cell type, with neuronal chromatin displaying higher regional variability than that of non-neurons. Among our findings is an open chromatin region (OCR) specific to neurons of the striatum. When placed in the mouse, a human sequence derived from this OCR recapitulates the cell-type and regional expression pattern predicted by our ATAC-seq experiments. Furthermore, differentially accessible chromatin overlaps with the genetic architecture of neuropsychiatric traits and identifies differences in molecular pathways and biological functions. By leveraging transcription factor binding analysis, we identify protein coding and long noncoding RNAs (lncRNAs) with cell-type and brain region specificity. Our data provides a valuable resource to the research community and we provide this human brain chromatin accessibility atlas as an online database “Brain Open Chromatin Atlas (BOCA)” to facilitate interpretation.

2018-06-21 | GSE96949 | GEO

RNA-Seq and ATAC-Seq of HEK239T cell line carrying different genotypes at rs4420550 by CRISPR/Cas9 editing

Project description:Background: Genome-wide association studies (GWAS) have reported hundreds of genomic loci associated with schizophrenia, yet identifying the functional risk variations is a key step in elucidating the underlying mechanisms. Methods: We applied multiple bioinformatics and molecular approaches, including expression quantitative trait loci (eQTL) analyses, epigenome signature identification, luciferase reporter assay, chromatin conformation capture (3C), homology-directed genome editing by CRISPR/Cas9, RNA-sequencing (RNA-Seq) and assay for transposase-accessible chromatin using sequencing (ATAC-Seq). Results: We found that the schizophrenia GWAS risk variations at 16p11.2 were significantly associated with mRNA levels of multiple genes in human brain, and one of the leading eQTL genes, MAPK3, located ~200-kb away from these risk variations in the genome. Further analyses based on the epigenome marks in human brain and cell lines suggested that a noncoding single nucleotide polymorphism (SNP) rs4420550 (p=2.36×10–9 in schizophrenia GWAS) was within a DNA enhancer region, which was validated via in vitro luciferase reporter assays. The 3C experiment showed that the rs4420550 region physically interacted with the MAPK3 promoter and TAOK2 promoter. Precise CRISPR/Cas9 editing of single base pair in cells followed by RNA-Seq further confirmed the regulatory effects of rs4420550 on the transcription of 16p11.2 genes, and ATAC-Seq demonstrated that rs4420550 affected chromatin accessibility at the 16p11.2 region. The rs4420550-[A/A] cells showed significantly higher proliferation rates compared with rs4420550-[G/G] cells. Conclusions: These results together suggest that rs4420550 is a functional risk variation, and this study illustrates an example of comprehensive functional characterization of schizophrenia GWAS risk loci.

2020-10-01 | GSE152177 | GEO

Activity-Dependent Transcriptional Program in NGN2+ Neurons Enriched for Genetic Risk for Brain-Related Disorders

Project description:We generated human-induced pluripotent stem cell (hiPSC) derived neurons isolated from six childhood-onset schizophrenia (COS) cases and five healthy controls. To measured the transcriptional and epigenomic changes following neuronal activation with KCl, we harvested these cells one and six hours after stimulation with 50mM KCl and under non-stimulating conditions, followed by RNA-seq and ATAC-seq profiling. We comprehensively characterized activity-dependent changes in gene expression and gene regulatory element activity (chromatin accessibility) in hiPSC-derived neurons. After one hour of KCl induced depolarization, neurons invoked substantial activity-dependent changes in the expression of genes regulating synaptic functions, some of which are known to be perturbed in neuropsychiatric diseases, including schizophrenia and autism spectrum disorder. By capturing changes in chromatin accessibility, we extended our analysis to activity-dependent gene regulatory elements, captured by changes in chromatin accessibility, and also found significant heritability enrichment for schizophrenia variants in the activity-induced enhancers. Our framework not only offers an alternative approach to study the mechanisms of COS but also adds to converging evidence that activity-induced expression changes mediated by the activity of regulatory elements might contribute to schizophrenia risk.

2023-07-14 | GSE203082 | GEO

CircTulp4 functions in Alzheimer’s disease pathogenesis by regulating its parental gene Tulp4

Project description:Here, we systematically investigated circRNAs in the APP/PS1 model mouse brain through deep RNA-sequencing. We report that circRNAs are markedly enriched in the brain and that several circRNAs exhibit differential expression between wild-type and APP/PS1 mice. We characterized one abundant circRNA, circTulp4, derived from Intron1 of the gene Tulp4. To investigate the effect of CircTulp4 on chromatin status, we used ATAC-seq to investigate the chromatin accessibility upon CircTulp4 knockdown.

2021-02-28 | E-MTAB-9919 | biostudies-arrayexpress

In-situ cell-type specific chromatin topologies in the brain revealed by genome architecture mapping

Project description:We report the application of genome architecture mapping in specific cell types in mouse brain. We generated cell-type specific chromatin contact maps in mouse dopaminergic neurons from the midbrain ventral tegmental area (VTA DN), pyramidal glutamatergic neurons from the cornus ammonis 1 region of the hippocampus (CA1 PGN), and non-neuronal post-mitotic oligodendrocytes from the somatosensory cortex (SSC_Olig). We explored cell-type specific chromatin topologies genome-wide at multiple genomic scales. Our data demonstrates that chromatin organization is cell type specific and reflects cell specialization at all genomic scales.

2021-08-27 | GSE148792 | GEO

In-situ cell-type specific chromatin topologies in the brain revealed by genome architecture mapping [ATAC-seq]

2021-08-27 | GSE174024 | GEO

Genome-wide transcriptome analysis of human iPSC-derived healthy control vs schizophrenia developmental glutamatergic neurons.

Project description:We report changes in gene expression in schizophrenia developmental glutamatergic neurons by genome-wide transcriptome analysis.

2022-12-31 | GSE184102 | GEO

A comparative atlas of single-cell chromatin accessibility in the human brain

Project description:A comparative atlas of single-cell chromatin accessibility in the human brainRecent advances in single-cell transcriptomics have illuminated the diverse neuronal and glial cell types within the human brain. However, the regulatory programs governing cell identity and function remain unclear. Using a single-nucleus assay for transposase-accessible chromatin using sequencing (ATAC-seq), we explored open chromatin landscapes across 1.1 million cells in 42 brain regions from three adults. Integrating this data unveiled 107 distinct cell types and their specific utilization of 544,735 candidate cis-regulatory DNA elements (cCREs) in the human genome. Nearly a third of the cCREs demonstrated conservation and chromatin accessibility in the mouse brain cells. We reveal strong links between specific brain cell types and neuropsychiatric disorders including schizophrenia, bipolar disorder, Alzheimer’s disease (AD), and major depression, and have developed deep learning models to predict the regulatory roles of noncoding risk variants in these disorders.

2023-10-04 | GSE244618 | GEO

Allele-specific open chromatin in human neurons elucidates functional noncoding disease variants

Project description:ASoC variants are prevalent and cell type-specific ASoC variants were over-represented in intergenic regions and active enhancers. The collection includes ATAC-Seq and RNA-Seq data that were taken from human iPS cells and their derived neuronal cells (neural progenitor cells, cortical glutamatergic neurons, GABAergic neurons, and dopaminergic neurons).

2020-05-05 | GSE129017 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data