Trichostatin A decreases the levels of MeCP2 expression and phosphorylation and increases its chromatin binding affinity

Good, Katrina V; Paz, Alexia Martínez de; Tyagi, Monica; Cheema, Manjinder S.; Thambirajah, Anita A.; Gretzinger, Taylor L.; Stefanelli, Gilda; Chow, Robert L.; Krupke, Oliver A.; Hendzel, Michael J.; Missiaen, Kristal; Underhill, D. Alan; Landsberger, Nicoletta; Ausió, Juan

doi:10.1080/15592294.2017.1380760

Cited by 12 publications

(14 citation statements)

References 103 publications

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“…Since different HDACis target various HDAC classes, this allowed us to explore the effects of individual HDACs on the expression of MeCP2. As shown in Figure 5, treatment with HDACis resulted in reduced MeCP2 levels, as reported before 30 . Treatment with Tubastin-A, Mocetinostat or Entinostat reduces MeCP2 levels in both cell lines.…”

Section: Hdacis Affect Mecp2 Expressionsupporting

confidence: 83%

HDAC inhibitors rescue MeCP2^T158Mspeckles in a high content screen

Lata,

Steegmans,

Kellens

et al. 2023

Preprint

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Rett syndrome (OMIM 312750) is a rare neurodevelopmental disorder caused byde novomutations in the Methyl-CpG Binding Protein 2 (MeCP2) gene located on the X-Chromosome, typically affecting girls. Currently, available therapy for Rett Syndrome is only symptomatic. Rett syndrome symptoms first appear between 6 to 18 months of age, characterized by microcephaly and lack of motor coordination being the most prevalent. The disease continues to progress until adulthood when it reaches a stationary phase. More than 800 different mutations causing Rett syndrome have been described, yet the most common is T158M (9% prevalence), located in the Methyl-Binding domain (MBD) of MeCP2. Due to its importance for DNA binding through recognition of methylated CpG, mutations in the MBD have a significant impact on the stability and function of MeCP2. MeCP2 is a nuclear protein and accumulates in liquid-liquid phase condensates visualized as speckles in NIH3T3 by microscopy. We developed a high content phenotypic assay, detecting fluorescent MeCP2 speckles in NIH3T3 cells. The assay allows to identify small molecules that stabilize MeCP2-T158M and phenotypically rescue speckle formation. To validate the assay, a collection of 3572 drugs was screened, including FDA-approved drugs, compounds in clinical trials and biologically annotated tool compounds. 18 hits were identified showing at least 25% of rescue of speckles in the mutant cell line while not affecting wild-type MeCP2 speckles. Primary hits were confirmed in a dose response assay and in a thermal shift assay with recombinant MeCP2. One class of identified hits represents histone deacetylase inhibitors (HDACis) showing 25% speckle rescue of mutant MeCP2 without toxicity. This screening strategycan be expanded to additional compound libraries and support novel drug discovery.

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Section: Hdacis Affect Mecp2 Expressionsupporting

confidence: 83%

HDAC inhibitors rescue MeCP2^T158Mspeckles in a high content screen

Lata,

Steegmans,

Kellens

et al. 2023

Preprint

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“…Activation of neurons leads to the decreased CpG methylation of the Bdnf promoter region and dissociation of the MeCP2-mSin3A-HDAC1 silencing complex [ 25 ]. Besides, MeCP2, which expression is reduced upon TSA treatment [ 81 ], binds to the inner nuclear membrane lamin B receptor [ 82 ]. Therefore the association of transcriptionally inactive Bdnf to the nuclear lamina and its detachment upon TSA treatment may be dependent on MeCP2 protein.…”

Section: Discussionmentioning

confidence: 99%

The interplay of seizures-induced axonal sprouting and transcription-dependent Bdnf repositioning in the model of temporal lobe epilepsy

et al. 2021

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The Brain-Derived Neurotrophic Factor is one of the most important trophic proteins in the brain. The role of this growth factor in neuronal plasticity, in health and disease, has been extensively studied. However, mechanisms of epigenetic regulation of Bdnf gene expression in epilepsy are still elusive. In our previous work, using a rat model of neuronal activation upon kainate-induced seizures, we observed a repositioning of Bdnf alleles from the nuclear periphery towards the nuclear center. This change of Bdnf intranuclear position was associated with transcriptional gene activity. In the present study, using the same neuronal activation model, we analyzed the relation between the percentage of the Bdnf allele at the nuclear periphery and clinical and morphological traits of epilepsy. We observed that the decrease of the percentage of the Bdnf allele at the nuclear periphery correlates with stronger mossy fiber sprouting—an aberrant form of excitatory circuits formation. Moreover, using in vitro hippocampal cultures we showed that Bdnf repositioning is a consequence of transcriptional activity. Inhibition of RNA polymerase II activity in primary cultured neurons with Actinomycin D completely blocked Bdnf gene transcription and repositioning occurring after neuronal excitation. Interestingly, we observed that histone deacetylases inhibition with Trichostatin A induced a slight increase of Bdnf gene transcription and its repositioning even in the absence of neuronal excitation. Presented results provide novel insight into the role of BDNF in epileptogenesis. Moreover, they strengthen the statement that this particular gene is a good candidate to search for a new generation of antiepileptic therapies.

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“…Interestingly, prenatal exposure to VPA displayed enhanced miR-132 whereas decrease of MeCP2 mRNA in embryonic brain [ 71 ]. Likewise, upregulated miR-132 in contrast to suppressed MeCP2 was observed in TSA treated NIH/3T3 cells [ 73 ], suggesting it would be possible VPA regulates MeCP2 expression through regulation of miR-132 levels.…”

Section: Discussionmentioning

confidence: 99%

Dual mechanisms for the regulation of brain-derived neurotrophic factor by valproic acid in neural progenitor cells

Jin

Park

et al. 2018

Korean J Physiol Pharmacol

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Autism spectrum disorders (ASDs) are neurodevelopmental disorders that share behavioral features, the results of numerous studies have suggested that the underlying causes of ASDs are multifactorial. Behavioral and/or neurobiological analyses of ASDs have been performed extensively using a valid model of prenatal exposure to valproic acid (VPA). Abnormal synapse formation resulting from altered neurite outgrowth in neural progenitor cells (NPCs) during embryonic brain development has been observed in both the VPA model and ASD subjects. Although several mechanisms have been suggested, the actual mechanism underlying enhanced neurite outgrowth remains unclear. In this study, we found that VPA enhanced the expression of brain-derived neurotrophic factor (BDNF), particularly mature BDNF (mBDNF), through dual mechanisms. VPA increased the mRNA and protein expression of BDNF by suppressing the nuclear expression of methyl-CpG-binding protein 2 (MeCP2), which is a transcriptional repressor of BDNF. In addition, VPA promoted the expression and activity of the tissue plasminogen activator (tPA), which induces BDNF maturation through proteolytic cleavage. Trichostatin A and sodium butyrate also enhanced tPA activity, but tPA activity was not induced by valpromide, which is a VPA analog that does not induce histone acetylation, indicating that histone acetylation activity was required for tPA regulation. VPA-mediated regulation of BDNF, MeCP2, and tPA was not observed in astrocytes or neurons. Therefore, these results suggested that VPA-induced mBDNF upregulation was associated with the dysregulation of MeCP2 and tPA in developing cortical NPCs.

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Trichostatin A decreases the levels of MeCP2 expression and phosphorylation and increases its chromatin binding affinity

Cited by 12 publications

References 103 publications

HDAC inhibitors rescue MeCP2^T158Mspeckles in a high content screen

HDAC inhibitors rescue MeCP2^T158Mspeckles in a high content screen

The interplay of seizures-induced axonal sprouting and transcription-dependent Bdnf repositioning in the model of temporal lobe epilepsy

Dual mechanisms for the regulation of brain-derived neurotrophic factor by valproic acid in neural progenitor cells

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Trichostatin A decreases the levels of MeCP2 expression and phosphorylation and increases its chromatin binding affinity

Cited by 12 publications

References 103 publications

HDAC inhibitors rescue MeCP2T158Mspeckles in a high content screen

HDAC inhibitors rescue MeCP2T158Mspeckles in a high content screen

The interplay of seizures-induced axonal sprouting and transcription-dependent Bdnf repositioning in the model of temporal lobe epilepsy

Dual mechanisms for the regulation of brain-derived neurotrophic factor by valproic acid in neural progenitor cells

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HDAC inhibitors rescue MeCP2^T158Mspeckles in a high content screen

HDAC inhibitors rescue MeCP2^T158Mspeckles in a high content screen