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Transcriptome analysis of a MECP2 conditional KO mouse model

ABSTRACT: Rett syndrome is a severe neurodevelopmental condition that rsults primarily from mutations in the MECP2 gene. MECP2 is known to function as both a transcriptional activator and transcriptional repressor. However, it remains unclear how transcriptional dysregulation resulting from MECP2 mutations lead to the Rett syndrome phenotype. Multiple mouse models have been generated to investigate the function of MECP2 in vivo. Remarkably, despite the neurodevelopmental phenotype characteristic of Rett syndrome, temporal conditional MECP2 knock-out mouse models with MECP2 deletion induced postnatally recapitulate the Rett-syndrome-like phenotype in mouse. Here we investigated gene expression changes in 22-weeks old mice following conditional MECP knock-out at 12 weeks by RNA-sequencing. Consistent with previous data, we identify mild gene expression changes following MECP2 knock-out. These data could prove valuable in future studies comparing conditional MECP2 knock-out at distinct time points and in additional brain regions, and can also serve for investigating alternative splicing changes resulting from MECP2 conditional deletion.

ORGANISM(S): Mus musculus

PROVIDER: GSE112663 | GEO | 2018/04/05

REPOSITORIES: GEO

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Unraveling autophagic imbalances and therapeutic insights in Mecp2-deficient models

Project description:Loss of function mutations in MECP2are associated to Rett syndrome (RTT), a severe neurodevelopmental disease. Mainly working as a transcriptional regulator, MECP2 absence leads to gene expression perturbations resulting in deficits of synaptic function and neuronal activity. In addition, RTT patients and mouse models suffer from a complex metabolic syndrome, suggesting that related cellular pathways might contribute to neuropathogenesis. Along this line, autophagy is critical in sustaining developing neuron homeostasis by breaking down dysfunctional proteins, lipids, and organelles. Here, we investigated the autophagic pathway in RTT and found reduced content of autophagic vacuoles in Mecp2 knock-out neurons. This correlates with defective lipidation of LC3B-II probably caused by a deficiency of the autophagic membrane lipid phosphatidylethanolamine. The administration of the autophagy inducer trehalose recovers LC3B lipidation, autophagosomes content in knock-out neurons, and ameliorates their morphology, neuronal activity and synaptic ultrastructure. Moreover, we provide evidence for attenuation of motor and exploratory impairment in Mecp2 knock-out mice upon trehalose administration. Overall, our findings open new perspectives for neurodevelopmental disorders therapies based on the concept of autophagy modulation.

2024-08-26 | GSE271893 | GEO

Transcriptional landscape of different brain regions in a Rett syndrome mouse model

Project description:We propose to investigate differential gene expression in Hippocampus and Frontal cortex of MeCP2 knock-out to gain more resolution on transcriptomic changes that occur in the Rett syndrome mouse model

2018-09-30 | GSE60219 | GEO

Swapping the DNA binding domain of MeCP2 with that of MBD2 to abolish binding to non-CG methlyation results in RTT-like phenotypes in mice [RNA-seq]

Project description:Mutations in the MECP2 gene cause the profound neurological disorder Rett syndrome. MeCP2 protein is an epigenetic reader that recruits the NCOR1/2 corepressor complexes to methylated cytosine in its canonical CG setting, but also to methylated CA motifs, which are abundant in neurons but rare in other cell types. In this study we set out to test the biological significance of this non-canonical mode of DNA binding. To achieve this, we replaced the endogenous MeCP2 DNA binding domain with that of MBD2, which only binds mCG. Knock-in mice expressing the hybrid “MM2” protein created by this domain-swap displayed severe Rett syndrome-like phenotypes. This indicates that binding to mCA, specifically the mCAC trinucleotide, is critical for normal brain function and it offers a plausible explanation for the delayed onset of Rett syndrome, due to the coincident late accumulation of mCAC and its cognate interpreter, MeCP2. We show that the small subset of genes aberrantly expressed in both Mecp2-null and MM2 mice is strikingly enriched for genes implicated in neurological disorders, highlighting targets with potential relevance to the Rett syndrome phenotype

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Swapping the DNA binding domain of MeCP2 with that of MBD2 to abolish binding to non-CG methlyation results in RTT-like phenotypes in mice [ATAC-seq]

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Genome-wide Analysis Reveals Mecp2-dependent Regulation of MicroRNAs in a Mouse Model of Rett Syndrome

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2010-09-29 | E-GEOD-24329 | biostudies-arrayexpress

Long non-coding RNAs expression study of a Rett syndrome mouse model

Project description:In order to identify some lncRNA potentially involved in Rett syndrome we performed a mouse lncRNA expression microarray on whole brain samples coming from wild-type and MeCP2 Knock-out littermates. We found 2 lncRNAs directly bound by MeCP2 and upregulated in KO samples. We then focused on AK081227 because it overlaps with Gabrr2. The expression of this GABA receptor and the overlapping AK081227 are inversely correlated in thalamus, suggesting the long non-coding is regulating his own host. Whole brain total RNA was extracted from two Wild type mice (P60) and two MeCP2 KO littermates (P60)

2013-10-03 | E-GEOD-43689 | biostudies-arrayexpress

Transcription profiling of human super frontal gyrus (post mortem brain) from Rett syndrome patients and age sex matched controls reveals FXYD1, an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice

Project description:Rett syndrome (RTT, OMIM 312750) is a severe X-linked neurodevelopmental disorder linked to heterozygous de novo mutations in the MECP2 gene. MECP2 encodes methyl-CpG-binding protein 2 (MeCP2), which represses gene transcription by binding to 5-methylcytosine residues in symmetrically positioned CpG dinucleotides. The disorder is almost exclusively diagnosed in females, because males affected by the disease usually die perinatally due to severe encephalopathy. Direct MeCP2 target genes underlying the neuropathogenesis of RTT remain largely unknown.

2007-11-02 | E-GEOD-6955 | biostudies-arrayexpress

Long non-coding RNAs expression study of a Rett syndrome mouse model

2013-10-03 | GSE43689 | 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.

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Wild-type and Mecp2 -/y callosal projection neurons

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