Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Loss of neuronal 3D chromatin organization causes transcriptional and behavioral deficits related to serotonergic dysfunction [ChIP-seq]

ABSTRACT: The interior of the neuronal cell nucleus is a highly organized 3-dimensional (3D) structure in which regions of the genome that are millions of bases apart participate in specialized sub-structures with dedicated functions. To investigate neuronal chromatin organization and dynamics in vivo, we generated bitransgenic mice that express histone GFP-tagged H2B in principal neurons of the forebrain. Surprisingly, the expression of this chimeric histone in mature neurons causes chromocenter declustering and disrupts the association of heterochromatin with the nuclear lamina. The loss of these structures does not affect neuronal viability but is associated with specific transcriptional and behavioral deficits related to serotonergic dysfunction. Overall, our results demonstrate that the 3D-organization of chromatin in the neuronal nucleus supports an additional level of epigenetic regulation of gene expression that critically influences neuronal function and indicate that some loci associated with neuropsychiatric disorders may be particularly sensitive to changes in chromatin architecture.

ORGANISM(S): Mus musculus

PROVIDER: GSE56809 | GEO | 2014/07/18

SECONDARY ACCESSION(S): PRJNA244660

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Loss of neuronal 3D chromatin organization causes transcriptional and behavioral deficits related to serotonergic dysfunction [ChIP-seq]

Project description:The interior of the neuronal cell nucleus is a highly organized 3-dimensional (3D) structure in which regions of the genome that are millions of bases apart participate in specialized sub-structures with dedicated functions. To investigate neuronal chromatin organization and dynamics in vivo, we generated bitransgenic mice that express histone GFP-tagged H2B in principal neurons of the forebrain. Surprisingly, the expression of this chimeric histone in mature neurons causes chromocenter declustering and disrupts the association of heterochromatin with the nuclear lamina. The loss of these structures does not affect neuronal viability but is associated with specific transcriptional and behavioral deficits related to serotonergic dysfunction. Overall, our results demonstrate that the 3D-organization of chromatin in the neuronal nucleus supports an additional level of epigenetic regulation of gene expression that critically influences neuronal function and indicate that some loci associated with neuropsychiatric disorders may be particularly sensitive to changes in chromatin architecture. Genome-wide profiling by high throughput sequencing of H3K27me3 in the adult hippocampus of CaMKII-tTA/tetO-H2BGFP (H2BGFP) and their wild-type littermates mice (WT). Chromatin immunoprecipitation (ChIP) was carried out using pooled hippocampal tissue from 3 mice (one hippocampus per mouse). One DNA library was constructed per genotype. Each DNA library was prepared from pooled immunoprecipitated DNA from 4 independent ChIP assays. In total, tissue from 12 different mice was used to prepare each DNA library. 60% of a lane was used to perform single end (1x50bp) multiplex sequencing in HiSeq 2500 apparatus (Illumina). Each library, was sequenced in duplicate (in two independent sequencing runs. Technical replicates).

2014-07-18 | E-GEOD-56809 | biostudies-arrayexpress

Loss of neuronal 3D chromatin organization causes transcriptional and behavioral deficits related to serotonergic dysfunction

Project description:The interior of the eukaryotic cell nucleus is a highly organized 3D structure. In mature hippocampal and cortical pyramidal neurons, transcriptionally silent DNA is typically compacted in a few clusters referred to as chromocenters that are strongly stained with DNA intercalating agents like DAPI and whose function is still uncertain. We found that this 3D structure was severely disrupted by the incorporation of the chimeric histone H2BGFP into neuronal chromatin. Experiments in inducible and forebrain restricted bitransgenic mice demonstrated that the expression of this histone alters the higher-order organization of neuronal heterochromatin and causes a complex behavioral phenotype that includes hyperactivity, and social interaction, prepulse inhibition and cognitive defects. This phenotype was associated with highly specific transcriptional deficits that affected several serotonin receptor genes located at the edge of gene desert regions. Pharmacological and electrophysiological experiments indicate that this epigenetically-induced hyposerotonergic state may underlie the behavioral defects. Our results suggest a new role for perinuclear heterochromatin and chromocenter organization in the epigenetic regulation of neuronal gene expression and mental illness. We used microarrays to detect differential gene expression in transgenic mice expressing histone H2BGFP in the forebrain. We obtained triplicate samples (biological replicates) of either genotype (wild-type and H2BGFP mice). Each sample contained pooled total RNA from the hippocampi of 2 three-month old genotype-matched mice.

2014-07-18 | E-GEOD-48437 | biostudies-arrayexpress

Loss of neuronal 3D chromatin organization causes transcriptional and behavioral deficits related to serotonergic dysfunction [expression]

2014-07-18 | GSE48437 | GEO

Reorganization of postmitotic neuronal chromatin accessibility for maturation of serotonergic identity

Project description:Assembly of transcriptomes encoding unique neuronal identities requires selective accessibility of transcription factors to cis-regulatory sequences in nucleosome-embedded postmitotic chromatin. Yet, the mechanisms controlling postmitotic neuronal chromatin accessibility are poorly understood. Here, we show that unique distal enhancers define the Pet1 neuron lineage that generates serotonin (5-HT) neurons. Heterogeneous single cell chromatin landscapes are established early in postmitotic Pet1 neurons and reveal the putative regulatory programs driving Pet1 neuron subtype identities. Distal enhancer accessibility is highly dynamic as Pet1 neurons mature, suggesting the existence of regulatory factors that reorganize postmitotic neuronal chromatin. We find that Pet1 and Lmx1b control chromatin accessibility to select Pet1-lineage specific enhancers for 5-HT neurotransmission. Additionally, these factors are required to maintain chromatin accessibility during early maturation suggesting that postmitotic neuronal open chromatin is unstable and requires continuous regulatory input. Together our findings reveal postmitotic transcription factors that reorganize accessible chromatin for neuron specialization.

2022-04-14 | GSE185737 | GEO

Extensive long-range polycomb interactions and weak compartmentalization are hallmarks of human neuronal 3D genome

Project description:Chromatin architecture regulates gene expression and shapes cellular identity, particularly in neuronal cells. Specifically, polycomb group (PcG) proteins enable establishment and maintenance of neuronal cell type by reorganizing chromatin into repressive domains that limit the expression of fate-determining genes and sustain distinct gene expression patterns in neurons. Here, we map the 3D genome architecture in neuronal and non-neuronal cells isolated from the Wernicke's area of four human brains and comprehensively analyze neuron-specific aspects of chromatin organization. We find that genome segregation into active and inactive compartments is greatly reduced in neurons compared to other brain cells. Furthermore, neuronal Hi-C maps reveal strong long-range interactions, forming a specific network of PcG-mediated contacts in neurons that is nearly absent in other brain cells. These interacting loci contain developmental transcription factors with repressed expression in neurons and other mature brain cells. But only in neurons, they are rich in bivalent promoters occupied by H3K4me3 histone modification together with H3K27me3, which points to a possible functional role of PcG contacts in neurons. Importantly, other layers of chromatin organization also exhibit distinct structure in neurons, which corroborates with increased cohesin levels in neurons and therefore might be attributed to elevated neuronal loop extrusion activity.

2024-03-26 | GSE229816 | GEO

Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration [Mate-Pair]

Project description:Persistent DNA double-strand breaks (DSBs) in neurons are an early pathological hallmark of neurodegenerative diseases including Alzheimer’s Disease (AD) with the potential to disrupt genome integrity. We show increased mosaic structural variations and gene fusions in neurons burdened with DSBs in the CK-p25 inducible mouse model of neurodegeneration. Next, we used full-transcript single-nucleus RNA-seq across 47 human post-mortem prefrontal cortex and find that excitatory neurons in AD are enriched for mosaic gene fusions. In addition, gene fusions are particularly enriched in excitatory neurons with senescence and DNA repair gene signatures. Neurons enriched for DSBs also have elevated levels of cohesin along with progressive multiscale disruption of the 3D genome organization aligned with transcriptional changes in synaptic and neuronal development genes. Overall, this study demonstrates the disruption of genome stability and the 3D genome organization by DSBs in neurons as pathological steps in the progression of neurodegenerative diseases.

2023-09-27 | GSE227444 | GEO

Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration [Hi-C]

Project description:Persistent DNA double-strand breaks (DSBs) in neurons are an early pathological hallmark of neurodegenerative diseases including Alzheimer’s Disease (AD), with the potential to disrupt genome integrity. We used single-nucleus RNA-seq in human post-mortem prefrontal cortex samples and found that excitatory neurons in AD were enriched for somatic mosaic gene fusions. Gene fusions were particularly enriched in excitatory neurons with DNA damage repair and senescence gene signatures. In addition, somatic genome structural variations and gene fusions were enriched in neurons burdened with DSBs in the CK-p25 mouse model of neurodegeneration. Neurons enriched for DSBs also had elevated levels of cohesin along with progressive multiscale disruption of the 3D genome organization aligned with transcriptional changes in synaptic, neuronal development, and histone genes. Overall, this study demonstrates the disruption of genome stability and the 3D genome organization by DSBs in neurons as pathological steps in the progression of neurodegenerative diseases.

2023-09-27 | GSE227443 | GEO

Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration [BLISS]

Project description:Persistent DNA double-strand breaks (DSBs) in neurons are an early pathological hallmark of neurodegenerative diseases including Alzheimer’s Disease (AD), with the potential to disrupt genome integrity. We used single-nucleus RNA-seq in human post-mortem prefrontal cortex samples and found that excitatory neurons in AD were enriched for somatic mosaic gene fusions. Gene fusions were particularly enriched in excitatory neurons with DNA damage repair and senescence gene signatures. In addition, somatic genome structural variations and gene fusions were enriched in neurons burdened with DSBs in the CK-p25 mouse model of neurodegeneration. Neurons enriched for DSBs also had elevated levels of cohesin along with progressive multiscale disruption of the 3D genome organization aligned with transcriptional changes in synaptic, neuronal development, and histone genes. Overall, this study demonstrates the disruption of genome stability and the 3D genome organization by DSBs in neurons as pathological steps in the progression of neurodegenerative diseases.

2023-09-27 | GSE227438 | GEO

Growth cone localization of the mRNA encoding a chromatin regulator modulates neurite outgrowth

Project description:Neurons exploit local mRNA translation and retrograde transport of transcription factors to regulate gene expression in response to signaling events at distal neuronal ends. Whether epigenetic factors could also be involved in such regulation is not known. We report that the mRNA encoding the HMGN5 chromatin binding protein localizes to growth cones of both neuronal-like cells and of hippocampal neurons, where it has the potential to be translated, and that HMGN5 can be retrogradely transported into the nucleus along neurites. Loss of HMGN5 function induces transcriptional changes and impairs neurite outgrowth while HMGN5 overexpression induces neurite outgrowth and chromatin decompaction. Interestingly, control of both neurite outgrowth and chromatin structure is dependent on growth cone localization of Hmgn5 mRNA. Our results provide the first evidence that mRNA localization and local translation might serve as a mechanism to couple the dynamic neuronal outgrowth process with chromatin regulation in the nucleus.

2015-04-17 | PXD001070 | Pride

A Constitutive Heterochromatic Region Shapes Genome Organization and Impacts Gene Expression in Neurospora crassa [RNA-Seq]

Project description:Genome organization is essential for proper function, including gene expression. In metazoan genome organization, chromatin loops and Topologically Associated Domains (TADs) facilitate local gene clustering, while chromosomes form distinct nuclear territories characterized by compartmentalization of silent heterochromatin at the nuclear periphery and active euchromatin in the nucleus center. A similar hierarchical organization occurs in the fungus Neurospora crassa where its seven chromosomes form a Rabl conformation, where heterochromatic centromeres and telomeres independently cluster at the nuclear membrane, while interspersed heterochromatic loci in Neurospora aggregate across megabases of linear genomic distance for forming TAD-like structures. However, the role of individual heterochromatic loci in normal genome organization and function is unknown. Here, we examined the genome organization of a Neurospora strain harboring a ~41 kilobase facultative (temporarily silent) heterochromatic region deletion, as well as the genome organization of a strain deleted of a ~110 kilobase permanently silent constitutive heterochromatic region. While the facultative heterochromatin deletion had little effect on local chromatin structure, the constitutive heterochromatin deletion altered local TAD-like structures, gene expression, and the predicted 3D genome structure by qualitatively repositioning genes into the nucleus center. Our work elucidates the role of individual heterochromatic regions for genome organization and function.

2024-06-10 | GSE269230 | 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