A novel pathogenic mutation of MeCP2 impairs chromatin association independent of protein levels
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1015718 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26046304_1.fastq.gz | Fastqsanger.gz | |||
| SRR26046304_2.fastq.gz | Fastqsanger.gz | |||
| SRR26046305_1.fastq.gz | Fastqsanger.gz | |||
| SRR26046305_2.fastq.gz | Fastqsanger.gz | |||
| SRR26046306_1.fastq.gz | Fastqsanger.gz |
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Project description:Loss-of-function mutations in MECP2 cause Rett Syndrome (RTT), a severe neurological disorder that mainly affects girls. Mutations in MECP2 do occur in males occasionally and typically cause severe encephalopathy and premature lethality. Recently, we identified a missense mutation c.353G>A, p.Gly118Glu (G118E) in a young boy who suffered from progressive motor dysfunction and developmental delay. To determine whether this variant causes the clinical symptoms and study its functional consequences, we established two disease models, including patient-derived iPSCs and a knock-in mouse line. Given that G118E mutation is in the DNA binding domain of MeCP2 and could potentially disrupt its chromatin association, we performed Cut&Run using WT and G118E mouse cortical tissue to characterize the genome wide binding pattern of WT and mutant MeCP2 proteins. We observed a reduction of DNA binding of G118E MeCP2 in the known MeCP2 target loci, as well as in a genome-wide manner.
2023-11-13 | GSE243009 | GEO
Project description:Loss-of-function mutations in MECP2 cause Rett syndrome (RTT), a severe neurological disorder that mainly affects girls. Mutations in MECP2 do occur in males occasionally and typically cause severe encephalopathy and premature lethality. Recently, we identified a missense mutation (c.353G>A, p.Gly118Glu [G118E]), which has never been seen before in MECP2, in a young boy who suffered from progressive motor dysfunction and developmental delay. To determine whether this variant caused the clinical symptoms and study its functional consequences, we established two disease models, including human neurons from patient-derived iPSCs and a knock-in mouse line. G118E mutation partially reduces MeCP2 abundance and its DNA binding, and G118E mice manifest RTT-like symptoms seen in the patient, affirming the pathogenicity of this mutation. Using live-cell and single-molecule imaging, we found that G118E mutation alters MeCP2's chromatin interaction properties in live neurons independently of its effect on protein levels. Here we report the generation and characterization of RTT models of a male hypomorphic variant and reveal new insight into the mechanism by which this pathological mutation affects MeCP2's chromatin dynamics. Our ability to quantify protein dynamics in disease models lays the foundation for harnessing high-resolution single-molecule imaging as the next frontier for developing innovative therapies for RTT and other diseases.
| S-EPMC10691473 | biostudies-literature
Project description:Previous studies suggested that MeCP2 binds to linker DNA and competes with linker histone H1 to regulate chromatin structure, but this hypothesis has never been tested in vivo. Here, we expressed Flag-tagged H1.0 in forebrain excitatory neurons in mice and performed ChIP-Seq to reveal H1.0 distribution and its relationship with MeCP2. Unexpectedly, we detected no major change in H1.0 upon MeCP2 depletion, revealing that MeCP2 functions independent of linker H1.0.
2018-05-28 | GSE107519 | GEO
Project description:Previous studies suggested that MeCP2 binds to linker DNA and competes with linker histone H1 to regulate chromatin structure, but this hypothesis has never been tested in vivo. Here, we expressed Flag-tagged H1.0 in forebrain excitatory neurons in mice and performed ChIP-Seq to reveal H1.0 distribution and its relationship with MeCP2. Unexpectedly, we detected no major change in H1.0 upon MeCP2 depletion, revealing that MeCP2 functions independent of linker H1.0.
2018-05-28 | GSE95471 | GEO
Project description:Mutations of MECP2 (Methyl-CpG Binding Protein 2) cause Rett Syndrome. As a chromatin associated multifunctional protein, how MeCP2 integrates external signals and regulates neuronal function remain unclear. While neuronal activity-induced phosphorylation of MeCP2 at serine 421 (S421) has been reported, the full spectrum of MeCP2 phosphorylation together with the in vivo function of such modifications are yet to be revealed. Here we report the identification of several novel MeCP2 phosphorylation sites in normal and epileptic brains from multiple species. We demonstrate that serine 80 (S80) phosphorylation of MeCP2 is critical as its mutation into alanine (S80A) in transgenic knock-in mice leads to locomotor deficits. S80A mutation attenuates MeCP2 chromatin association at several gene promoters in resting neurons and leads to transcription changes of a small number of genes. Calcium influx in neurons causes dephosphorylation at S80, potentially contributing to its dissociation from the chromatin. We postulate that phosphorylation of MeCP2 modulates its dynamic function in neurons transiting between resting and active states within neural circuits that underlie behaviors. E 15.5 Mecp2 -/y cortical neurons were infected with lentivirus expressing wild-type and S80A mutant MeCP2 at similar protein expression level. 2 biological independent samples and dye swap were used for this set (GSM367413) and replicate 2 set (GSM367414).
2009-02-10 | E-GEOD-14715 | biostudies-arrayexpress
Project description:MeCP2 is transcriptional regulator, however the mechanism is not fully understood. This study uses various levels of MeCP2 in human neurons to discover mechanism of MeCP2 action. The transcriptional data are used to correlate with methylation status of genes.
2019-06-27 | GSE126640 | GEO
Project description:Mutations of MECP2 (Methyl-CpG Binding Protein 2) cause Rett Syndrome. As a chromatin associated multifunctional protein, how MeCP2 integrates external signals and regulates neuronal function remain unclear. While neuronal activity-induced phosphorylation of MeCP2 at serine 421 (S421) has been reported, the full spectrum of MeCP2 phosphorylation together with the in vivo function of such modifications are yet to be revealed. Here we report the identification of several novel MeCP2 phosphorylation sites in normal and epileptic brains from multiple species. We demonstrate that serine 80 (S80) phosphorylation of MeCP2 is critical as its mutation into alanine (S80A) in transgenic knock-in mice leads to locomotor deficits. S80A mutation attenuates MeCP2 chromatin association at several gene promoters in resting neurons and leads to transcription changes of a small number of genes. Calcium influx in neurons causes dephosphorylation at S80, potentially contributing to its dissociation from the chromatin. We postulate that phosphorylation of MeCP2 modulates its dynamic function in neurons transiting between resting and active states within neural circuits that underlie behaviors.
2009-02-10 | GSE14715 | GEO
Project description:Genome Wide Distribution of Linker Histone H1.0 is Independent of MeCP2
| PRJNA420486 | ENA
Project description:MeCP2 globally regulates gene expression in the brain. One example is Growth-differentiation factor 11 (Gdf11), which is down-regulated upon loss of MeCP2 and up-regulated upon gain of MeCP2. To assess if MeCP2 binds near the Gdf11 locus we performed CUT&RUN for MeCP2 in Mecp2-knockout or MECP2-transgenic hippocampus. To assess if a repressive histone modification (H3K27me3) was concordantly changed we profiled H3k27me3 in these same matched tissues.
2023-02-23 | GSE213752 | GEO
Project description:MECP2-R270X transgenic mice (TG) and MECP2-G273X TG mice were generated in the Zoghbi Lab. These mice express the respective truncated form of MeCP2 tagged with GFP at the C-terminus from a transgenic human PAC containing all known regulatory sequences. These transgenes were maintained on a wild-type pure FVB background. For experiments each transgenic line was crossed by Mecp2 null mice (Mecp2 tm1.1Bird) on a pure 129SvEv background and the resulting male F1 hybrid progeny (FVB;129SvEv) that lacked endogenous MeCP2 expression but expressed either transgene (Mecp2 -/y; MECP2-R270X TG or Mecp2-/y; MECP2-G273X TG) were used for ChIP-Seq analysis. Whole brain from either the R270X mice (Mecp2 -/y; MECP2-R270X TG) or the G273X mice (Mecp2 -/y; MECP2-G273X TG) was formaldehyde crosslinked and purified chromatin was immunoprecipitated with anti-GFP antibody (Abcam ab6556).
2013-03-12 | GSE36536 | GEO