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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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RNA-Seq of WT and Mecp2 KO cerebellum after transplantation with Neural/Precursor Cells (NPCs)

ABSTRACT: RTT represents the first genetic cause of severe intellectual disability in girls and although potentially treatable, no cure is currently available. The identification of a valid therapy is delayed by the need of maintaining physiological MeCP2 levels and by the limited comprehension of its roles. Neural precursor cell (NPC) transplantation has already been proved safe and efficacious in many neurological disorders. Particularly, in neurodegenerative conditions, their mechanism of action mainly relies on cell replacement; however, when neurodegeneration is absent, it has been demonstrated that NPCs act by a so-called “bystander” mechanism, by releasing of a plethora of molecules, including inflammatory cytokines, chemokines, trophic factors and stem cell regulators. These factors exert immunomodulatory and neuroprotective effects, and can also modulate synaptic plasticity. Willing to come with a novel cure for RTT, starting from our data indicating the therapeutic potential of NPCs in Mecp2 deficient animals and neurons, we aim at identifying the molecules and/or pathways involved in their therapeutic benefit, a required step for moving the therapy from the bench to the bedside. By bulk RNA sequencing (RNA-seq), we analyzed the transcriptional profile of the cerebellum derived from WT and Mecp2 KO animals, injected with NPCs or vehicle (PBS) at post-natal day (P) 45. Analysis was conducted 20 days after transplantation (at P60). n=5-6 animals/exp.group.

INSTRUMENT(S): Illumina HiSeq 2500

ORGANISM(S): Mus musculus

SUBMITTER: Angelisa Frasca

PROVIDER: E-MTAB-12813 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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RNA-Seq of WT and Mecp2 KO hippocampus after transplantation with Neural/Precursor Cells (NPCs)

Project description:RTT represents the first genetic cause of severe intellectual disability in girls and although potentially treatable, no cure is currently available. The identification of a valid therapy is delayed by the need of maintaining physiological MeCP2 levels and by the limited comprehension of its roles. Neural precursor cell (NPC) transplantation has already been proved safe and efficacious in many neurological disorders. Particularly, in neurodegenerative conditions, their mechanism of action mainly relies on cell replacement; however, when neurodegeneration is absent, it has been demonstrated that NPCs act by a so-called “bystander” mechanism, by releasing of a plethora of molecules, including inflammatory cytokines, chemokines, trophic factors and stem cell regulators. These factors exert immunomodulatory and neuroprotective effects, and can also modulate synaptic plasticity. Willing to come with a novel cure for RTT, starting from our data indicating the therapeutic potential of NPCs in Mecp2 deficient animals and neurons, we aim at identifying the molecules and/or pathways involved in their therapeutic benefit, a required step for moving the therapy from the bench to the bedside. By bulk RNA sequencing (RNA-seq), we analyzed the transcriptional profile of the hippocampus derived from WT and Mecp2 KO animals, injected with NPCs or vehicle (PBS) at post-natal day (P) 45. Analysis was conducted 20 days after transplantation (at P60). n=5-6 animals/exp.group.

2024-08-27 | E-MTAB-14403 | biostudies-arrayexpress

MeCP2 binds to mCH as neurons mature, influencing transcription and onset of Rett syndrome [mRNA-Seq]

Project description:The postnatal neurodevelopmental disorder Rett syndrome (RTT) is caused by mutations in the gene encoding Methyl-CpG-binding Protein 2 (MeCP2). Despite decades of research, it remains unclear how MeCP2 actually regulates transcription or why RTT features appear only 6-18 months after birth. We examined MeCP2 binding to methylated cytosine in the CH context (mCH, where H = A, C, or T) in the adult mouse brain and found that MeCP2 binds these mCH sites, influencing nucleosome positioning and transcription. Strikingly, this pattern is unique to the mature nervous system, as it requires the increase in mCH after birth to reveal differences in MeCP2 binding to mCG, mCH, and non-methylated DNA elements. This study provides insight into the molecular mechanism governing MeCP2 targeting and how this targeting might contribute to the delayed onset of RTT symptoms. mRNA-Seq were conducted from 7-week-old hypothalamus from MeCP2 knockout mice and their age and genetic background matched wild types control mice. Additonal mRNA-Seq were conducted from 7-week-old hypothalamus from MeCP2 transgenic mice and their age and genetic background matched wild types control mice.

2015-04-15 | E-GEOD-66870 | biostudies-arrayexpress

RNA-Seq of wild-type murine primary cortical neurons co-cultured in a transwell-based system with Mecp2 knock-out or wild-type cortical murine astrocytes

Project description:Rett syndrome (RTT; OMIM#312750) is a rare devastating neurodevelopmental disorder that represents the most common genetic cause of severe intellectual disability in girls. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene have been reported in over 95% cases of classical forms of RTT. Although initial studies supported a role for MeCP2 exclusively in neurons, recent data indicate a function also in astrocytes, which emerged as critical players involved in RTT pathogenesis through non-cell autonomous effects. Indeed, Mecp2 knock-out (KO) astrocytes cannot properly support neuronal maturation of wilt-type (WT) neurons and our data demonstrated a detrimental effect also on synaptogenesis and synaptic maintainence. Nevertheless, the molecular mechanisms by which RTT astrocytes can impact on neuronal health remains unknown. In comparison to previous studies exploring the transcriptomic and proteomic profiles of KO astrocytes per se, we used an indirect strategy to unveil the molecular mechanisms responsible for their negative action on neurons. We thus analysed the molecular pathways deregulated in WT neurons cultivated under the influence of KO (n=8) versus WT (n=7) astrocytes, in a transwell-based co-culture system, that allows the exchange of paracrine signals preventing cell-to-cell contact. Astrocytes were seeded on transwell inserts and transferred on neurons at Div0; the co-cultures were maintained until Div14. WT cortical neurons cultivated alone were also included (n=5).

2024-02-19 | E-MTAB-12393 | biostudies-arrayexpress

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

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

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

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.

2023-09-01 | GSE214547 | GEO

Multiplex Epigenome Editing of MECP2 to Rescue Rett Syndrome Neurons (WGBS)

2023-09-01 | GSE214549 | GEO

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

2023-09-01 | GSE214548 | GEO

MeCP2 binds to mCH as neurons mature, influencing transcription and onset of Rett syndrome [ChIP-Seq]

Project description:The postnatal neurodevelopmental disorder Rett syndrome (RTT) is caused by mutations in the gene encoding Methyl-CpG-binding Protein 2 (MeCP2). Despite decades of research, it remains unclear how MeCP2 actually regulates transcription or why RTT features appear only 6-18 months after birth. We examined MeCP2 binding to methylated cytosine in the CH context (mCH, where H = A, C, or T) in the adult mouse brain and found that MeCP2 binds these mCH sites, influencing nucleosome positioning and transcription. Strikingly, this pattern is unique to the mature nervous system, as it requires the increase in mCH after birth to reveal differences in MeCP2 binding to mCG, mCH, and non-methylated DNA elements. This study provides insight into the molecular mechanism governing MeCP2 targeting and how this targeting might contribute to the delayed onset of RTT symptoms. MeCP2 ChIP-Seq were conducted from ~ 7-week-old hypothalamus tissues from Mecp2-/y; MECP2-EGFP mice.

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