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Genetic and epigenetic determinants of reactivation of Mecp2 and the inactive X chromosome in neural stem cells (RNA-seq)

ABSTRACT: Genetic and epigenetic determinants of reactivation of Mecp2 and the inactive X chromosome in neural stem cells (RNA-seq)

PROVIDER: PRJNA699456 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13627888.fastq.gz	Fastqsanger.gz
	SRR13627889.fastq.gz	Fastqsanger.gz
	SRR13627890.fastq.gz	Fastqsanger.gz
	SRR13627891.fastq.gz	Fastqsanger.gz
	SRR13627892.fastq.gz	Fastqsanger.gz

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Genetic and epigenetic determinants of reactivation of Mecp2 and the inactive X chromosome in neural stem cells [RNA-seq]

Project description:Rett Syndrome is a neurodevelopmental disorder in girls that is caused by heterozygous inactivation of the chromatin remodeler gene MECP2. Rett Syndrome may therefore be treated by reactivation of the wild type copy of MECP2 from the inactive X chromosome. Most studies that model Mecp2 reactivation have used mouse fibroblasts rather than neural cells, which would be critical for phenotypic reversal, and rely on fluorescent reporters that lack adequate sensitivity. Here, we present a mouse model system for monitoring Mecp2 reactivation that is more sensitive and versatile than any bioluminescent and fluorescent system currently available. The model consists of neural stem cells derived from female mice with a dual reporter system where MECP2 is fused to NanoLuciferase and TdTomato on the inactive X chromosome. We show by bioluminescence and fluorescence that Mecp2 is synergistically reactivated by 5-Aza treatment and Xist knockdown. As expected, other genes on the inactive X chromosome are also reactivated, the majority of which overlaps with genes reactivated early during reprogramming of mouse embryonic fibroblasts to iPSCs. Genetic and epigenetic features such as CpG density, SINE elements, distance to escapees and CTCF binding are consistent indicators of reactivation, whereas different higher order chromatin areas are either particularly prone or resistant to reactivation. Our MeCP2 reactivation monitoring system thereby suggests that genetic and epigenetic features on the inactive X chromosome affect reactivation of its genes, irrespective of cell type or procedure of reactivation.

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Genetic and epigenetic determinants of reactivation of Mecp2 and the inactive X chromosome in neural stem cells [MeD-seq]

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Genetic and epigenetic determinants of reactivation of Mecp2 and the inactive X chromosome in neural stem cells

Project description:Genetic and epigenetic determinants of reactivation of Mecp2 and the inactive X chromosome in neural stem cells

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Genetic and epigenetic determinants of reactivation of Mecp2 and the inactive X chromosome in neural stem cells [MeD-seq]

Project description:Genetic and epigenetic determinants of reactivation of Mecp2 and the inactive X chromosome in neural stem cells [MeD-seq]

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A screen for reactivation of MeCP2 on the inactive X-chromosome identifies BMP/TGF-b superfamily as a regulator of maintenance of XIST expression

Project description:X-chromosome inactivation (XCI) is an epigenetic phenomenon that renders one of the two X-chromosomes in female cells transcriptionally silent, ensuring that X-linked gene dosage matches that in males, who have only one copy of the X chromosome. When a mutation of an X-linked gene is heterozygous, as it is in most girls with Rett syndrome, a neurodevelopmental disorder caused by a mutation MeCP2 gene, the presence of the mutated allele on the active X chromosome entails transcriptional inactivation of the wild type allele on the inactive X, resulting in complete loss of gene function. Reactivation of the silenced wild-type copy of MeCP2 therefore presents a potential therapeutic strategy for Rett syndrome. To identify genes that silence MeCP2 on the Xi that could prove useful therapeutic targets, we carried out a screen for genes whose downregulation reactivated a MeCP2 reporter on the Xi. The 30 genes we have identified comprise seven functional groups revealing a genetic circuitry required for maintenance of X-chromosome inactivation in differentiated cells and a large number of targets suitable for pharmacologic intervention.

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Genetic and epigenetic determinants of reactivation of Mecp2 and the inactive X chromosome in neural stem cells.

Project description:Rett syndrome may be treated by reactivating the silent copy of Mecp2 from the inactive X chromosome in female cells. Most studies that model Mecp2 reactivation have used mouse fibroblasts rather than neural cells, which would be critical for phenotypic reversal, and rely on fluorescent reporters that lack adequate sensitivity. Here, we present a mouse model based on a dual bioluminescent and fluorescent reporter to assess the level of reactivation of Mecp2 and the inactive X chromosome by treating neural stem cells with 5-azacytidine and Xist knockdown. We show that reactivation of Mecp2 and other X-linked genes correlates with CpG density, with distance from escapees, and, very strongly, with the presence of short interspersed nuclear elements. In addition, X-linked genes reactivated in neural stem cells overlap substantially with early reactivating genes by induced pluripotent stem cell reprogramming of fibroblasts or neuronal progenitors, indicating that X chromosome reactivation follows similar paths regardless of the technique or cell type used.

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Genetic and epigenetic determinants of reactivation of Mecp2 and the inactive X chromosome in neural stem cells

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