Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Pharmacological reversal of synaptic and network pathology in human MECP2-KO neurons and cortical organoids

ABSTRACT: Duplication or deficiency of the X-linked MECP2 gene reliably produces profound neurodevelopmental impairment. MECP2 mutations are almost universally responsible for Rett syndrome (RTT), and particular mutations and cellular mosaicism of MECP2 may underlie the spectrum of RTT symptomatic severity. No clinically approved treatments for RTT are currently available, but human pluripotent stem cell technology offers a platform to identify neuropathology and test candidate therapeutics. Using a strategic series of increasingly complex human stem cell-derived technologies, including human neurons, MECP2-mosaic neurospheres to model RTT female brain mosaicism, and cortical organoids, we identified synaptic dysregulation downstream from knockout of MECP2 and screened select pharmacological compounds for their ability to treat this dysfunction. Two lead compounds, Nefiracetam and PHA 543613, specifically reversed MECP2-knockout cytologic neuropathology. The capacity of these compounds to reverse neuropathologic phenotypes and networks in human models supports clinical studies for neurodevelopmental disorders in which MeCP2 deficiency is the predominant etiology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160146 | GEO | 2020/10/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Activity-dependent aberrations in gene expression and alternative splicing in a mouse model of Rett syndrome

Project description:Rett syndrome (RTT) is a severe neurodevelopmental disorder that is caused by mutations in the gene methyl-CpG-binding-protein-2 (MECP2). However, the molecular mechanism by which these mutations mediate the RTT neuropathology remains enigmatic. In this study, we stimulated MeCP2-null cortical neurons (in vitro) and brains (in vivo) of a RTT mouse model to explore the effect of the loss of MeCP2 function on the activity-dependent transcriptomes of the cortex and hippocampus, respectively, using RNA-seq. These analyses revealed that the loss of MeCP2 results in aberrant global pattern of gene expression, characterized predominantly by higher levels of expression of activity-dependent genes, and anomalous alternative splicing events, specifically in response to neuronal activity.

2018-05-22 | GSE113477 | GEO

Transcription profiling of human differentiated vs. undifferentiated SH-SY5Y cells transfected with a MeCP2 (transcriptional repressor) decoy to investigate the neurodevelopmental disorder Rett syndrome

Project description:Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder caused by mutations in MECP2, encoding methyl-CpG-binding protein 2. MeCP2 is a transcriptional repressor elevated in mature neurons and is predicted to be required for neuronal maturation by regulating multiple target genes. Identifying primary gene targets in either Mecp2-deficient mice or human RTT brain has proven to be difficult, perhaps because of the transient requirement for MeCP2 during neuronal maturation. In order to experimentally control the timing of MeCP2 expression and deficiency during neuronal maturation, human SH-SY5Y cells undergoing mature neuronal differentiation were transfected with methylated MeCP2 oligonucleotide decoy to disrupt the binding of MeCP2 to endogenous targets. Genome-wide expression microarray analysis identified all four known members of the inhibitors of differentiation or inhibitors of DNA-binding (ID1, ID2, ID3 and ID4) subfamily of helix-loop-helix genes as novel neuronal targets of MeCP2. Chromatin immunoprecipitation analysis confirmed binding of MeCP2 near or within the promoters of ID1, ID2 and ID3, and quantitative RT-PCR confirmed increased expression of all four Id genes in Mecp2-deficient mouse brain. All four ID proteins were significantly increased in Mecp2-deficient mouse and human RTT brain using immunofluorescence and laser scanning cytometric analyses. Because of their involvement in cell differentiation and neural development, ID genes are ideal primary targets for MeCP2 regulation of neuronal maturation that may explain the molecular pathogenesis of RTT.

2007-10-26 | E-GEOD-4600 | biostudies-arrayexpress

Transcriptomic analysis of mutant MECP2 human neural progenitor cells

Project description:Rett Syndrome (RTT) is a severe neurological disorder predominantly affecting females, caused by mutations in the methyl CpG binding protein 2 (MECP2) gene. Understanding the pathophysiology of RTT at a cellular and molecular level is crucial for the development of targeted therapies. Our project aims to dissect the molecular underpinnings of RTT using a novel in vitro model system based on a commercially available human neural progenitor cell line, ReNCell. We have engineered multiple distinct ReNCell lines to mimic specific genetic alterations associated with RTT, providing a robust platform for mechanistic studies and drug screening. This cell line carries a point mutation in the MECP2 gene (R133C), a common mutation in RTT patients, which alters the function of the MeCP2 protein. The model will allow us to study the impact of this mutation on neural development and function at a cellular level, providing insights into the disease's neuropathology.

2024-11-17 | E-MTAB-14046 | biostudies-arrayexpress

Inhibition of BET proteins rescues neural defects in Rett syndrome [DNA methylation profile]

Project description:Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein 2 (MeCP2). Cellular heterogeneity in the brain confounds the understanding of RTT etiology. To date, how MeCP2 mutation affects defined cell types in human brain remains unclear, and effective therapeutics for RTT is lacking. Here we show that cell-type-specific transcriptome impairment and JQ1-mediated rescue in RTT cells from dorsal and ventral human forebrain organoids. We find that MeCP2 mutation severely impairs human cortical interneurons (INs). Dysregulation of MeCP2-BRD4 ChIP regulatory axis and three-dimensional genome architecture are critically involved in the abnormal transcription in RTT INs, and JQ1 strongly rescues RTT INs by resetting the aberrant chromatin binding of BRD4 ChIP. Finally, JQ1 alleviates RTT-like phenotypes in mice. These data demonstrate that BRD4 ChIP dysregulation is a critical driver for RTT etiology and targeting BRD4 ChIP is an effective therapeutic opportunity for RTT.

2020-06-12 | GSE149094 | GEO

Inhibition of BET proteins rescues neural defects in Rett syndrome [scRNA-seq]

Project description:Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein 2 (MeCP2). Cellular heterogeneity in the brain confounds the understanding of RTT etiology. To date, how MeCP2 mutation affects defined cell types in human brain remains unclear, and effective therapeutics for RTT is lacking. Here we show that cell-type-specific transcriptome impairment and JQ1-mediated rescue in RTT cells from dorsal and ventral human forebrain organoids. We find that MeCP2 mutation severely impairs human cortical interneurons (INs). Dysregulation of MeCP2-BRD4 regulatory axis and three-dimensional genome architecture are critically involved in the abnormal transcription in RTT INs, and JQ1 strongly rescues RTT INs by resetting the aberrant chromatin binding of BRD4. Finally, JQ1 alleviates RTT-like phenotypes in mice. These data demonstrate that BRD4 dysregulation is a critical driver for RTT etiology and targeting BRD4 is an effective therapeutic opportunity for RTT.

2020-06-12 | GSE117512 | GEO

Inhibition of BET proteins rescues neural defects in Rett syndrome [RNA-seq]

2020-06-12 | GSE117511 | GEO

Inhibition of BET proteins rescues neural defects in Rett syndrome [HiC-seq]

2020-06-12 | GSE117509 | GEO

Inhibition of BET proteins rescues neural defects in Rett syndrome [ChIP-seq]

2020-06-12 | GSE117508 | GEO

Inhibition of BET proteins rescues neural defects in Rett syndrome [ATAC-seq]

2020-06-12 | GSE117507 | GEO

Identifying targets of MeCP2 during neuronal maturational differentiation

Project description:Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder caused by mutations in MECP2, encoding methyl-CpG binding protein 2. MeCP2 is a transcriptional repressor elevated in mature neurons and is predicted to be required for neuronal maturation by regulating multiple target genes. Identifying primary gene targets in either Mecp2-deficient mice or human RTT brain has proven to be difficult, perhaps because of the transient requirement for MeCP2 during neuronal maturation. In order to experimentally control the timing of MeCP2 expression and deficiency during neuronal maturation, human SH-SY5Y cells undergoing mature neuronal differentiation were transfected with methylated MeCP2 oligonucleotide decoy to disrupt the binding of MeCP2 to endogenous targets. Genome-wide expression microarray analysis identified all four known members of the inhibitors of differentiation or inhibitors of DNA binding (ID1, ID2, ID3 and ID4) subfamily of helix-loop-helix (HLH) genes as novel neuronal targets of MeCP2. Chromatin immunoprecipitation analysis confirmed binding of MeCP2 near or within the promoters of ID1, ID2 and ID3, and quantitative RT-PCR confirmed increased expression of all four Id genes in Mecp2-deficient mouse brain. All four ID proteins were significantly increased in Mecp2-deficient mouse and human RTT brain using immunofluorescence and laser scanning cytometric analyses. Because of their involvement in cell differentiation and neural development, ID genes are ideal primary targets for MeCP2 regulation of neuronal maturation that may explain the molecular pathogenesis of RTT. Keywords: Neuronal Differentiation, Targets of MeCP2, Rett syndrome.

2006-06-15 | GSE4600 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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