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MRNA-Seq of the CA1 hippocampal subregion from 3 month old animals injected with JQ1 (50mg/kg) i.p. and mRNA-Seq of CA1 of 8-10 month old APP/PS1-21 transgenic animals injected with JQ1 (50mg/kg) i.p.

ABSTRACT: Histone acetylation is essential for memory formation and provides a drug target to treat dementia. The histone acetylation landscape is shaped by chromatin writer and eraser proteins. In contrast, little is known about the neural activity of chromatin readers that link chromatin state to cellular function. Here, we tested the effect of JQ1 – a small molecule inhibitor of the chromatin readers BRD2, BRD3, BRD4 and BRDT – on associative and spatial memory tasks and on synaptic plasticity and found that it is able to enhance cognitive performance and long-term potentiation in wildtype animals and in a mouse model for amyloid deposition. JQ1 elicited a hippocampal gene expression program associated with ion channel activity, transcription and DNA repair. Our findings suggest that JQ1 could be used as a therapy against dementia and should be further tested in the context of learning and memory.

ORGANISM(S): Mus musculus

PROVIDER: GSE93796 | GEO | 2017/09/24

SECONDARY ACCESSION(S): PRJNA362358

REPOSITORIES: GEO

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Inhibition of BET proteins during adolescence affects prefrontal cortex development: relevance to schizophrenia

Project description:Background: The present study investigated a role of proteins from BET family (epigenetic readers) in schizophrenia-like abnormalities in MAM-E17 model of schizophrenia. Methods: An inhibitor of BET proteins, JQ1, was given during adolescence in postnatal days (P) 23-P30, and behavioral response (sensorimotor gating, recognition memory) and prefrontal cortex (mPFC) function (long-term potentiation (LTP), molecular and proteomic studies) were performed in adult males and females. Results: Deficits in sensorimotor gating and recognition memory were observed only in MAM-treated males. However, adolescent JQ1 treatment affected control, but MAM-treated groups in both sexes. Electrophysiological study showed an LTP impairment only in male MAM-treated animals, and JQ1 did not have any effect on LTP in the mPFC. In contrast, MAM did not affect immediate early gene expression (markers of neuronal and synaptic activity), but JQ1 altered them in both sexes. Proteomic study revealed alterations in MAM-treated groups only in males, while JQ1 affected both sexes. Conclusions: Prenatal MAM administration induced schizophrenia-like abnormalities only in males. In contrast, adolescent JQ1 treatment affected both sexes and induced behavioral changes in control groups, altered a markers of neuronal and synaptic activity and proteomic landscape in the mPFC of both groups (VEH- and MAM-treated). Thus, adolescent inhibition of BET family might change neuroplasticity in the mPFC.

2021-09-07 | PXD027050 | Pride

small RNA-Seq of the CA1 hippocampal subregion from 3 month and 20 month old animals treated orally with vehicle or SAHA

Project description:Aging and increased amyloid burden are major risk factors for cognitive diseases such as Alzheimer's Disease (AD). An effective therapy does not yet exist. Here we use mouse models for age-associated memory impairment and amyloid deposition to study transcriptome and cell type-specific epigenome plasticity at the systems level in the brain and in peripheral organs. We show that at the level of epigenetic gene-expression aging and amyloid pathology are associated with inflammation and impaired synaptic function in the hippocampal CA1 region. While inflammation is associated with increased gene-expression that is linked to a subset of transcription factors, de-regulation of plasticity genes is mediated via different mechanisms in the amyloid and the aging model. Amyloid pathology impairs histone-acetylation and decreases expression of plasticity genes while aging affects differential splicing that is linked to altered H4K12 acetylation at the intron-exon junction in neurons but not in non-neuronal cells. We furthermore show that oral administration of the clinically approved histone deacetylase inhibitor Vorinostat not only restores spatial memory, but also exhibits an anti-inflammatory action and reinstates epigenetic balance and transcriptional homeostasis at the level of gene expression and exon usage. This is the first systems-level investigation of transcriptome plasticity in the hippocampal CA1 region in aging and AD models and of the effects of an orally dosed histone deacetylase inhibitor. Our data has important implications for the development of minimally invasive and cost-effective therapeutic strategies against age-associated cognitive decline. In fact, our data strongly suggest to test Vorinostat in patients suffering from AD.

2015-08-17 | GSE63944 | GEO

mRNA-Seq of the CA1 hippocampal subregion and liver from 3 month and 20 month old animals treated orally with vehicle or SAHA and mRNA-Seq of CA1 of 10 month old WT or APP/PS1-21 transgenic animals treated orally with vehicle or SAHA

2015-08-17 | GSE63943 | GEO

Thermal proteome profiling of JQ1

Project description:Goal of this experiment was the identification of proteins affected in their thermal stability by JQ1.

2018-05-02 | PXD008638 | Pride

2 Dimensional Thermal proteome profiling of JQ1

Project description:Goal of this experiment was the identification of proteins affected dose dependently in their thermal stability by JQ1.

2018-05-02 | PXD008626 | Pride

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2018-05-02 | PXD008637 | Pride

Differential gene expression in neuroblastoma cells after treatment with vehicle control, JQ1, panobinostat, or combination of JQ1 and panobinostat

Project description:The bromodomain inhibitor JQ1 and the histone deacetylase inhibitor panobinostat induce synergistic anticancer effects We analyzed whether JQ1 and panobinostat synergistically modulate gene expression Neuroblastoma SK-N-BE(2) cells were treated with vehicle control, 1 microM JQ1, 10 nM panobinostat, or combination of JQ1 and panobinostat for 6 hours, and subjected to differential gene expression studies with Affymetrix microarrays.

2015-12-31 | E-GEOD-68690 | biostudies-arrayexpress

Syngergistic Effect of JQ1 and Rapamycin for Treatment of Human Osteosarcoma

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2015-05-01 | E-GEOD-57203 | biostudies-arrayexpress

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Project description:Global mRNA expression profiles of murine primary PDAC cells following JQ1 or SAHA monotherapy as well as JQ1-SAHA combination therapy were collected using Affymetix mouse whole genome array (Mouse Genome 430A 2.0 Array) . Primary PDAC cells isolated from Ptf1aCre/+;Kras+/LSL-G12D;p53lox/lox (Kras;p53) mice were treated either with JQ1 (100 nM) or SAHA (2000 nM) or vehicle 10% (2-Hydroxypropyl)-β-cyclodextrin (Sigma-Aldrich) or as combination therapy with the indicated dosage for monotherapy. Total RNA isolation was performed after 6 hours of treatment. Primary PDAC cells from Ptf1aCre/+;Kras+/LSL-G12D;p53lox/lox (Kras;p53) mice treated either with JQ1, SAHA, vehicle or JQ1-SAHA combination were analyzed by global gene expression analysis.

2015-09-20 | E-GEOD-64836 | biostudies-arrayexpress

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2017-10-01 | GSE95513 | GEO

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