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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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

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 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.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Homo sapiens

SUBMITTER: Angelika Merkel

PROVIDER: E-MTAB-14047 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcriptomic analysis of mutant MECP2 human neural progenitor cells

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

Transcriptomic analysis of mutant MECP2 and NEAT1 human neural 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. This 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. One 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. The other line involves the knockdown of NEAT1, a long non-coding RNA known to be involved in the pathogenesis of several neurological disorders, including RTT. Recent studies suggest NEAT1 plays a critical role in the neuronal cellular response to MECP2 dysfunction. By reducing NEAT1 expression, we aim to elucidate its contribution to RTT pathology and explore its potential as a therapeutic target. Here we characterize the transcriptome of these cell lines, including the wild type (control), at the progenitor state and after 7 days of differentiation with three replicates each.

2024-11-17 | E-MTAB-14048 | biostudies-arrayexpress

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Project description:Rett syndrome (RTT) is a progressive neurodevelopmental disease often caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). The mechanisms by which impaired MeCP2 induces the pathological abnormalities in the brain is not understood. To understand the molecular mechanisms involved in disease onset, we used an RTT patient induced pluripotent stem cell (iPSC)-based model and applied an in-depth high-resolution quantitative mass spectrometry-based analysis during early stages of neuronal development. Our data provided evidence of proteomic alteration at developmental stages long before the phase that symptoms of RTT syndrome become apparent. Differential expression increased from early to late neural stem cell phases, although proteins involved in immunity, metabolic processes and calcium signaling were already affected at initial stages. This data can help development of new biomarkers and therapeutic approaches in RTT syndrome.

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Quantitative proteomics study of Mecp2 KO versus wild type mice

Project description:Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the transcriptional regulator MeCP2. RTT is characterized by having apparently normal development until 6-18 months, when a progressive decline in motor and language functions begins and breathing abnormalities and seizures present. Here we present the first proteomic analysis in a RTT mouse model. Examining whole cortex tissue in symptomatic males (Mecp2Jae/y) and wild-type littermates, we have identified 465 proteins significantly altered. Pathway analysis identified biological pathways ubiquitous to multiple cell types as well as cell type specific pathways, underscoring the contributions of multiple central nervous system (CNS) cell populations to the disease pathogenesis.

2017-11-02 | PXD006460 | Pride

Gene expression of blood and cerebellum of Mecp2-null and WT male mice

Project description:In order to find a relationship between gene expression of blood and brain in Rett Syndrome (RTT), we performed RNA sequencing on from cerebella and blood of 7 week-old male Mecp2-null mice (a model of RTT) and WT controls.

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Transcriptional regulation in pluripotent stem cells by Methyl CpG binding protein 2 (MeCP2)

Project description:Rett syndrome (RTT) is one of the most prevalent female mental disorders. De novo mutations in methyl CpG binding protein 2 (MeCP2) are a major cause of RTT. MeCP2 regulates gene expression as a transcription regulator as well as through long-range chromatin interaction. Because MeCP2 is present on the X chromosome, RTT is manifested in a X-linked dominant manner. Investigation using murine MeCP2 null models and post-mortem human brain tissues has contributed to understanding the molecular and physiological function of MeCP2. In addition, RTT models using human induced pluripotent stem cells derived from RTT patients (RTT-iPSCs) provide novel resources to elucidate the regulatory mechanism of MeCP2. Previously, we obtained clones of female RTT-iPSCs that express either wild type or mutant MECP2 due to the inactivation of one X chromosome. Reactivation of the X chromosome also allowed us to have RTT-iPSCs that express both wild type and mutant MECP2. Using these unique pluripotent stem cells, we investigated the regulation of gene expression by MeCP2 in pluripotent stem cells by transcriptome analysis. We found that MeCP2 regulates genes encoding mitochondrial membrane proteins. In addition, loss of function in MeCP2 results in de-repression of genes on the inactive X chromosome. Furthermore, we showed that each mutation in MECP2 affects a partly different set of genes. These studies suggest that fundamental cellular physiology is affected by mutations in MECP2 from very early fetal development and that a therapeutic approach targeting to unique forms of mutant MeCP2 is needed. RNA samples from normal ESCs/iPSCs, RTT-iPSCs and MeCP2 KD iPSCs were obtained. Gene expression of those cells were analyzed.

2013-10-25 | E-GEOD-51607 | biostudies-arrayexpress

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

2020-06-12 | GSE117508 | GEO

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

2020-06-12 | GSE117507 | GEO

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

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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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