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Prevention of MECP2 phosphorylation at S423 changes global transcription in primary cortical neurons co-cultured with BV2 cells upon LPS/IFNγ-induced activation.

ABSTRACT: Methyl-CpG-binding protein 2 (MECP2) is a transcriptional regulator critical for synaptic function. Dysfunction of synapses, in turn, as well as microglia-mediated neuroinflammation belong to the earliest pathological events in Alzheimer’s disease (AD). Functional versatility of MECP2, including its affinity for different binding partners, transcriptional regulation of different gene sets, and effects on neuronal plasticity, are modulated by post-translational modifications, such as phosphorylation. To characterize expression changes through blocking of MECP2 S80 and S423 phosphorylation in neuron-BV2 co-cultures upon induction of neuroinflammation, mouse primary cortical neurons were transduced with MECP2-WT and MECP2-S80A and MECP2-S423A phopsho-variants. Neuroinflammation was induced with LPS/IFNγ and the samples were subjected to RNA sequencing. In neurons co-cultured with BV2 cells, blocking of MECP2 S423 phosphorylation increased the expression of several genes important for neuron and synapse maintenance and protection upon inflammatory stress conditions. Blocking of S80 phosphorylation did not lead to major global expression changes.The results suggest that MECP2 S423 phosphorylation might play a role in activation of neuronal gene expression conveying neuroprotection under neuroinflammation related stress conditions.

ORGANISM(S): Mus musculus

PROVIDER: GSE166670 | GEO | 2021/02/13

REPOSITORIES: GEO

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Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological function

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

Effect of small molecules on activated BV2 microglia cell line

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Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological function

2009-02-10 | GSE14715 | GEO

Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function [ChIP-Seq]

Project description:Autism spectrum disorders such as Rett syndrome (RTT) have been hypothesized to arise from defects in experience-dependent synapse maturation. RTT is caused by mutations in MECP2, a nuclear protein that becomes phosphorylated at S421 in response to neuronal activation. We show here that disruption of MeCP2 S421 phosphorylation in vivo results in defects in synapse development and behavior, implicating activity-dependent regulation of MeCP2 in brain development and RTT. We investigated the mechanism by which S421 phosphorylation regulates MeCP2 function and show by chromatin immunoprecipitation-sequencing that this modification occurs on MeCP2 bound across the genome. The phosphorylation of MeCP2 S421 appears not to regulate the expression of specific genes; rather, MeCP2 functions as a histone-like factor whose phosphorylation may facilitateM-CM-^BM-BM- a genome-wide response of chromatin to neuronal activity during nervous system development. We propose that RTT results in part from a loss of this experience-dependent chromatin remodeling. To examine MeCP2 binding across the neuronal genome and where on the genome MeCP2 is phosphorylated at Serine 421 in response to neuronal activity we performed anti-total MeCP2 and anti-phospho-Serine 421 specific Chromatin immunoprecipitation from cultured cortical neurons that were either left unstimulated or membrane depolarized for 2 hours by addition of 55mM KCl to the media. ChIP DNA was verified for successful IP by qPCR then cloned and sequenced using ABI SOLiD system 4. ChIP was performed from E16 +7DIV disociated cortical cultures from one or two independent dissections using an anti-c-terminal antiserum recognizing MeCP2 independent of its phosphorylation state or with an anti-pS421 antiserum that specifically immunoprecipitates MeCP2 phosphorylated at serine 421. Samples were qPCR validated and sequenced using ABI SOLiD system 4 library preparation and sequencing.

2011-09-08 | E-GEOD-31951 | biostudies-arrayexpress

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2021-03-19 | GSE169175 | GEO

Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function [ChIP-Seq]

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2011-09-08 | GSE31951 | GEO

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Project description:We have developed an assay to test the neuroprotective properties of compounds using stem cell–derived motor neurons and astrocytes, together with activated microglia as a stress paradigm. Hit compounds were discovered and the transcriptional response on activated BV2 cells was tested.

2012-11-03 | GSE37612 | GEO

MeCP2 Represses the Activity of Topoisomerase IIβ in Long Neuronal Genes

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2023-11-15 | PXD046904 | Pride

Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function [visual cortex]

Project description:Autism spectrum disorders such as Rett syndrome (RTT) have been hypothesized to arise from defects in experience-dependent synapse maturation. RTT is caused by mutations in MECP2, a nuclear protein that becomes phosphorylated at S421 in response to neuronal activation. We show here that disruption of MeCP2 S421 phosphorylation in vivo results in defects in synapse development and behavior, implicating activity-dependent regulation of MeCP2 in brain development and RTT. We investigated the mechanism by which S421 phosphorylation regulates MeCP2 function and show by chromatin immunoprecipitation-sequencing that this modification occurs on MeCP2 bound across the genome. The phosphorylation of MeCP2 S421 appears not to regulate the expression of specific genes; rather, MeCP2 functions as a histone-like factor whose phosphorylation may facilitate a genome-wide response of chromatin to neuronal activity during nervous system development. We propose that RTT results in part from a loss of this experience-dependent chromatin remodeling. Gene expression analysis of RNA isolated from P17 mouse visual cortex was performed comparing global gene expression between Wild-Type and MeCP2 S421A knock-in mice. We isolated RNA from the visual cortex of 4 wild-type and 4 MeCP2 S421A littermate P17 Mice, and analyzed mRNA expression using the Affymetrix Mouse Gene 1.0 ST microarray platform.

2011-09-07 | E-GEOD-31850 | biostudies-arrayexpress

Prevention of MECP2 phosphorylation at S423 changes global transcription in primary cortical neurons co-cultured with BV2 cells upon LPS/IFNγ-induced activation.

Project description:Prevention of MECP2 phosphorylation at S423 changes global transcription in primary cortical neurons co-cultured with BV2 cells upon LPS/IFNγ-induced activation.

| PRJNA701569 | ENA

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