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Xi-reactivation: A mixed modality approach to MECP2 restoration for Rett Syndrome and other X-linked disorders

ABSTRACT: The X-chromosome harbors hundreds of disease genes whose associated diseases predominantly affect males. However, a subset — including neurodevelopmental disorders, Rett, Fragile X, and CDKL5 Syndromes — also affects females. These disorders lack disease-specific treatment. Because female cells carry two X-chromosomes, an emerging treatment strategy has been to reawaken the healthy allele on the inactive X (Xi). Here we focus on MECP2 restoration for Rett Syndrome and combinatorially target factors in the interactome of Xist, the noncoding RNA responsible for X-inactivation. We identify a mixed modality approach combining an Xist antisense oligonucleotide and a small molecule inhibitor of DNA methylation, which together achieve 30,000-fold MECP2 upregulation from the Xi in cultured cells. Combining a brain-specific genetic Xist ablation with short-term Aza treatment models the synergy in vivo without evident toxicity. The Xi is selectively reactivated. These experiments provide proof of concept for a mixed modality approach for treating X-linked disorders in females.

ORGANISM(S): Mus musculus

PROVIDER: GSE97077 | GEO | 2018/01/04

SECONDARY ACCESSION(S): PRJNA380634

REPOSITORIES: GEO

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Mus musculus

Project description:Xi-reactivation: A mixed modality approach to MECP2 restoration for Rett Syndrome and other X-linked disorders

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Xist RNA regulates remodeling of the Xi during B cell stimulation [Hi-C]

Project description:The inactive X (Xi) is formed by a process called X-Chromosome Inactivation (XCI), with Xist upregulation, retention of Xist RNA transcripts at the Xi, chromatin re-organization, and transcriptional silencing. Female lymphocytes have ‘dynamic’ XCI maintenance where Xist RNA is transcribed but absent from the Xi in naïve lymphocytes and re-localizes after in-vitro activation. How ‘dynamic’ XCI impacts Xi dosage and nuclear organization, or where Xist RNA interacts with the Xi is unknown. Here we find maintenance of Xi dosage and global structure despite the absence of Xist RNA in naïve B-cells. However, we identified 104 escape genes and observe a gain of de-novo TADs on the Xi. Stimulation-dependent Xi remodeling co-occurs with Xist RNA re-accumulation at the Xi, and loss of Xist increases TAD remodeling and decompacts the Xi in both naïve and stimulated B-cells. Altogether, these results reveal B-cell specific Xi plasticity which could underlie female-specific mechanisms in lymphocytes.

2024-12-31 | GSE212257 | GEO

Xist RNA regulates remodeling of the Xi during B cell stimulation [RNA-seq]

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Neuronal cytoskeletal gene dysregulation drives mechanical hypersensitivity in Rett Syndrome

Project description:This study investigated mechanisms of peripheral sensory abnormalities in Rett Syndrome using a MeCP2 knockout rat. Dramatic changes in peripheral innervation by DRG sensory neurons were observed in the knockout rats that strongly correlated with modality-specific sensory dysfunction. The cell-autonomous effect of MeCP2 mutation in DRG neurons disrupt axon growth mechanisms leading to the altered cutaneous innervation density. We performed RNA-Seq to compare the transcriptome of MeCP2 KO DRGs with that derived from wildtype littermates. This revealed profound impact of MeCP2 loss on axon growth regulatory pathways in sensory neurons. The findings will have significant impact on our understanding of sensory dysfunctions in Rett syndrome and Autism Spectrum Disorders at large.

2018-02-14 | GSE87855 | GEO

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

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 | GSE214549 | GEO

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

2023-09-01 | GSE214547 | GEO

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

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Cell type specific expression data from Mecp2 null mice

Project description:Human methyl-CpG-binding protein 2 (MeCP2) disruption causes Rett syndrome, an autistic disease prevalent in females. Previous microarray expression profiling studies using tissue homogenate samples from mouse model of the Rett syndrome revealed only modest changes in expression caused by the loss of Mecp2, making it difficult to identify etiology of the Rett syndrome. Here, we carried out cell type specific genome wide expression profiling of Mecp2 null mice in three neuronal cell types. We found a hot spot of Mecp2 affected genes in chromosome 11B3 syntenic to human chromosome 17p13 which has known associations to mental retardation. We also found Mecp2 affected genes are almost non-overlapping between cell types. Cell-adhesion category of genes, however, are commonly overrepresented, suggesting a possible etiology of Rett syndrome Keywords: cell type comparison, disease state analysis, genetic modification Transgenic mice lines which label subpopulations of neurons (G42: fast spiking Parvarbumin positive interneurons, YFPH: layer 5 thick tufted pyramidal neurons, TH: tyrosine hydroxylase positive locus coeruleus neurons) were used to obtain cell type specific expression profiles on Affymetrix microarrays. Females which carry Mecp2 null alleles (and one of the fluorescent alleles) were crossed with males (which may or may not carry one of the fluorescent alleles depending on whether the female has one or not). Male offsprings at around age P40 which carry fluorescent allele and Mecp2 null allele were used for experiments. Littermate males which carry fluorescent allele but not Mecp2 null allele were used for controls. 3 or 4 biological replicates were done for each condition.

2011-11-01 | E-GEOD-8720 | biostudies-arrayexpress

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.

2017-01-20 | GSE90685 | GEO

MeCP2 heterochromatin organization is modulated by arginine methylation and serine phosphorylation

Project description:Rett syndrome is a human intellectual disability disorder that is associated with mutations in the X-linked MECP2 gene. Theepigenetic reader MeCP2 binds to methylated cytosines on the DNA and regulates chromatin organization. We have shownpreviously that MECP2 Rett syndrome missense mutations are impaired in chromatin binding and heterochromatinreorganization. Here, we performed a proteomics analysis of post-translational modifications of MeCP2 isolated from adult mousebrain. We show that MeCP2 carries various post-translational modifications, among them phosphorylation on S80 and S421, whichlead to minor changes in either heterochromatin binding kinetics or clustering. We found that MeCP2 is (di)methylated on severalarginines and that this modification alters heterochromatin organization. Interestingly, we identified the Rett syndrome mutationsite R106 as a dimethylation site. In addition, co-expression of protein arginine methyltransferases 1 and 6 lead to a decrease ofheterochromatin clustering. Altogether, we identified and validated novel modifications of MeCP2 in the brain and show that thesecan modulate its ability to bind as well as reorganize heterochromatin, which may play a role in the pathology of Rett syndrome.

2022-10-15 | PXD033696 | Pride

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