Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice [NeuN+ hippocampal neurons]

ABSTRACT: Many Mendelian developmental disorders caused by coding variants in epigenetic regulators have now been discovered. Epigenetic regulators are broadly expressed, and each of these disorders typically exhibits phenotypic manifestations from many different organ systems. An open question is whether the chromatin disruption -- the root of the pathogenesis -- is similar in the different disease-relevant cell types. This is possible in principle, since all these cell-types are subject to effects from the same causative gene, that has the same kind of function (e.g. methylates histones) and is disrupted by the same germline variant. We focus on mouse models for Kabuki syndrome types 1 and 2, and find that the chromatin accessibility abnormalities in neurons are mostly distinct from those in B or T cells. This is not because the neuronal abnormalities occur at regulatory elements that are only active in neurons. Neurons, but not B or T cells, show preferential chromatin disruption at CpG islands and at regulatory elements linked to aging. A sensitive analysis reveals that the regions disrupted in B/T cells do exhibit chromatin accessibility changes in neurons, but these are very subtle and of uncertain functional significance. Finally, we identify a small set of regulatory elements disrupted in all three cell types. Our findings reveal the cellular-context-specific effect of variants in epigenetic regulators, and suggest that blood-derived episignatures may not be well-suited for understanding the mechanistic basis of neurodevelopment in Mendelian disorders of the epigenetic machinery.

ORGANISM(S): Mus musculus

PROVIDER: GSE239338 | GEO | 2023/07/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice [NeuN+ hippocampal neurons]

Project description:Many Mendelian developmental disorders caused by coding variants in epigenetic regulators have now been discovered. Epigenetic regulators are broadly expressed, and each of these disorders typically exhibits phenotypic manifestations from many different organ systems. An open question is whether the chromatin disruption -- the root of the pathogenesis -- is similar in the different disease-relevant cell types. This is possible in principle, since all these cell-types are subject to effects from the same causative gene, that has the same kind of function (e.g. methylates histones) and is disrupted by the same germline variant. We focus on mouse models for Kabuki syndrome types 1 and 2, and find that the chromatin accessibility abnormalities in neurons are mostly distinct from those in B or T cells. This is not because the neuronal abnormalities occur at regulatory elements that are only active in neurons. Neurons, but not B or T cells, show preferential chromatin disruption at CpG islands and at regulatory elements linked to aging. A sensitive analysis reveals that the regions disrupted in B/T cells do exhibit chromatin accessibility changes in neurons, but these are very subtle and of uncertain functional significance. Finally, we identify a small set of regulatory elements disrupted in all three cell types. Our findings reveal the cellular-context-specific effect of variants in epigenetic regulators, and suggest that blood-derived episignatures may not be well-suited for understanding the mechanistic basis of neurodevelopment in Mendelian disorders of the epigenetic machinery.

2024-04-03 | GSE263164 | GEO

Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice [CD90.2+ T cells, RNA-seq]

2024-04-03 | GSE263144 | GEO

Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice [CD90.2+ T cells]

2023-07-31 | GSE239337 | GEO

Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation - RNA-seq

Project description:The Mendelian Disorders of the Epigenetic Machinery (MDEMs) have emerged as a class of Mendelian disorders caused by loss-of-function variants in epigenetic regulators. Although each MDEM has a different causative gene, they exhibit several overlapping disease manifestations. Here, we hypothesize that this phenotypic convergence is a consequence of common abnormalities at the epigenomic level, which directly or indirectly lead to downstream convergence at the transcriptomic level. This implies that identifying abnormalities shared across multiple MDEMs could pinpoint locations where epigenetic variation is causally related to disease phenotypes. To test our hypothesis, we perform a comprehensive interrogation of chromatin (ATAC-Seq) and expression (RNA-Seq) states in B cells from mouse models of three MDEMs (Kabuki types 1&2 and Rubinstein-Taybi syndromes). We build on recent work in covariate-powered multiple testing to develop a new approach for the overlap analysis, which enables us to find extensive overlap primarily localized in gene promoters. We show that disruption of chromatin accessibility at promoters often leads to disruption of downstream gene expression, and identify a total of 463 loci and 249 genes commonly disrupted across the three MDEMs. As an example of how widespread dysregulation leads to specific phenotypes, we show that subtle expression alterations of multiple, directly relevant genes, collectively contribute to IgA deficiency in KS1 and RT. In contrast, we predict that KS2 does not have IgA deficiency, and confirm this pattern in mice. We propose that the joint study of MDEMs offers a principled approach for systematically mapping functional epigenetic variation in mammals.

2021-08-31 | GSE162176 | GEO

Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation - ATAC-seq

2021-08-31 | GSE162174 | GEO

NHGRI Mendelian Disorders Sequencing Centers

Project description:NHGRI Mendelian Disorders Sequencing Centers

| PRJNA158501 | ENA

Histone H3K27ac separates active from poised enhancers and predicts developmental state (gene expression data)

Project description:Developmental programs are controlled by transcription factors and chromatin regulators, which maintain specific gene expression programs through epigenetic modification of the genome. These regulatory events at enhancers contribute to the specific gene expression programs that determine cell state and the potential for differentiation into new cell types. While enhancer elements are known to be associated with certain histone modifications, and transcription factors, the relationship of these modifications to gene expression and developmental state has not been clearly defined. Here we interrogate the epigenetic landscape of enhancer elements in embryonic stem cells and several adult tissues in the mouse. We find that histone H3K27ac distinguishes active enhancers from inactive/poised enhancer elements, thus providing clues to current cell state and further developmental potential. Gene expression profiling was performed in mouse ES, NPC, liver, and pro-B

2010-10-31 | E-GEOD-23907 | biostudies-arrayexpress

Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation

Project description:Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation

| PRJNA680795 | ENA

Epigenetic and Genetic Profiling in Lymphoma

Project description:<p>Lymphomas are a prevalent and heterogeneous family of cancers arising in cells of the immune system. Drivers of lymphomagenesis include genomic rearrangements that juxtapose active regulatory elements with specific oncogene targets, as well as mutations affecting specific transcription factors and chromatin regulatory proteins. This study seeks to combine genome-wide genetic and epigenetic datasets to better understand mechanisms of oncogene dysregulation across distinct lymphoma types.</p>

| phs000939 | dbGaP

Dysregulation of NRSF/REST via EHMT1 is associated with psychiatric disorders

Project description:Genetic evidence indicates disrupted epigenetic regulation as a major risk factor for psychiatric disorders, but the molecular mechanisms that drive this association are undetermined. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a neurodevelopmental disorder (NDD) leading to ID, and is associated with schizophrenia. Here, we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. We further show that EHMT1 regulates NRSF/REST indirectly via repression of miRNA leading to aberrant neuronal gene regulation and neurodevelopment timing. Expression of a NRSF/REST mRNA that lacks the miRNA-binding sites restores neuronal gene regulation to EHMT1 deficient cells. Importantly, the EHMT1-regulated miRNA gene set with elevated expression is enriched for NRSF/REST regulators with an association for ID and schizophrenia. This reveals a molecular interaction between H3K9 dimethylation and NSRF/REST contributing to the aetiology of psychiatric disorders.

2023-05-01 | E-MTAB-10480 | biostudies-arrayexpress

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