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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptomic analysis of mutant MECP2 human neural progenitor cells

ABSTRACT: 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.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Homo sapiens

SUBMITTER: Angelika Merkel

PROVIDER: E-MTAB-14046 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Single cell transcriptomic analysis of mutant MECP2 human neural cells over a time-course of in vitro differentiation

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 is a complete knockout of MECP2, serving as a model to investigate the effects of total loss of MeCP2 function. This model helps in understanding the full spectrum of MeCP2's roles in neural development and maintenance, and in identifying compensatory mechanisms that could be targeted therapeutically. We capture the progenitor state (0 days), and differentiation states at 3, 7, 14, 21 and 30 days for both the MECP2 knockut and the corresponding wildtype.

2024-11-17 | E-MTAB-14047 | biostudies-arrayexpress

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

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Project description:Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by loss-of-function heterozygous mutations of MECP2. Reactivation of the silent wild-type MECP2 allele on the inactive X chromosome (Xi) represents a promising therapeutic opportunity for female RTT patients. Here, we applied a multiplex epigenome editing approach to reactivate MECP2 on Xi. Demethylation of the MECP2 promoter by dCas9-Tet1 with target sgRNA reactivated MECP2 on Xi in RTT hESCs without detectable off-target effects at the transcriptome level. Neurons derived from methylation edited RTT hESCs reversed the smaller soma size and electrophysiological abnormalities. Insulation of the methylation edited MECP2 locus in RTT neurons by dCpf1-CTCF with target crRNA stabilized MECP2 reactivation and rescued the RTT-related neuronal defects, providing a proof-of-concept study for multiplex epigenome editing to treat RTT.

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Multiplex Epigenome Editing of MECP2 to Rescue Rett Syndrome Neurons (ChIP-Seq)

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Multiplex Epigenome Editing of MECP2 to Rescue Rett Syndrome Neurons (RNA-Seq)

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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.

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

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