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Targeting Histone K4 Trimethylation for Treatment of Cognitive and Synaptic Deficits of Mouse Models of Alzheimer's Disease

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE180001 | GEO | 2021/07/14

REPOSITORIES: GEO

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Targeting histone K4 trimethylation for treatment of cognitive and synaptic deficits in mouse models of Alzheimer's disease.

Project description:Epigenetic aberration is implicated in aging and neurodegeneration. Using postmortem tissues from patients with Alzheimer's disease (AD) and AD mouse models, we have found that the permissive histone mark H3K4me3 and its catalyzing enzymes are significantly elevated in the prefrontal cortex (PFC). Inhibiting H3K4-specific methyltransferases with the compound WDR5-0103 leads to the substantial recovery of PFC synaptic function and memory-related behaviors in AD mice. Among the up-regulated genes reversed by WDR5-0103 treatment in PFC of AD mice, many have the increased H3K4me3 enrichment at their promoters. One of the identified top-ranking target genes, Sgk1, which encodes serum and glucocorticoid-regulated kinase 1, is also significantly elevated in PFC of patients with AD. Administration of a specific Sgk1 inhibitor reduces hyperphosphorylated tau protein, restores PFC glutamatergic synaptic function, and ameliorates memory deficits in AD mice. These results have found a novel epigenetic mechanism and a potential therapeutic strategy for AD and related neurodegenerative disorders.

| S-EPMC7725456 | biostudies-literature

Targeting Histone K4 Trimethylation for Treatment of Cognitive and Synaptic Deficits of Mouse Models of Alzheimer's Disease (ChIP-seq)

Project description:We performed chromatin immunoprecipitation sequencing (ChIPseq) to profile genome-wide occupancy of H3K4me3 in PFC from WT mice and P301S Tau mice

2021-07-14 | GSE179999 | GEO

Targeting Histone K4 Trimethylation for Treatment of Cognitive and Synaptic Deficits of Mouse Models of Alzheimer's Disease (RNA-seq)

Project description:We performed RNAseq experiments to examine genome-wide transcriptional changes in PFC of P301S Tau mice with or without WDR5-0103 treatment.

2021-07-14 | GSE179998 | GEO

Targeting Histone K4 Trimethylation for Treatment of Cognitive and Synaptic Deficits of Mouse Models of Alzheimer's Disease

Project description:Targeting Histone K4 Trimethylation for Treatment of Cognitive and Synaptic Deficits of Mouse Models of Alzheimer's Disease

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Targeting Histone K4 Trimethylation for Treatment of Cognitive and Synaptic Deficits of Mouse Models of Alzheimer's Disease (ChIP-seq)

Project description:Targeting Histone K4 Trimethylation for Treatment of Cognitive and Synaptic Deficits of Mouse Models of Alzheimer's Disease (ChIP-seq)

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Targeting Histone K4 Trimethylation for Treatment of Cognitive and Synaptic Deficits of Mouse Models of Alzheimer's Disease (RNA-seq)

Project description:Targeting Histone K4 Trimethylation for Treatment of Cognitive and Synaptic Deficits of Mouse Models of Alzheimer's Disease (RNA-seq)

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PRMT6-mediated methylation of R2 in histone H3 antagonizes H3 K4 trimethylation.

Project description:The arginine methyltransferase PRMT6 (protein arginine methyltransferase 6) has been shown recently to regulate DNA repair and gene expression. As arginine methylation of histones is an important mechanism in transcriptional regulation, we asked whether PRMT6 possesses activity toward histones. We show here that PRMT6 methylates histone H3 at R2 and histones H4/H2A at R3 in vitro. Overexpression and knockdown analysis identify PRMT6 as the major H3 R2 methyltransferase in vivo. We find that H3 R2 methylation inhibits H3 K4 trimethylation and recruitment of WDR5, a subunit of the MLL (mixed lineage leukemia) K4 methyltransferase complex, to histone H3 in vitro. Upon PRMT6 overexpression, transcription of Hox genes and Myc-dependent genes, both well-known targets of H3 K4 trimethylation, decreases. This transcriptional repression coincides with enhanced occurrence of H3 R2 methylation and PRMT6 as well as reduced levels of H3 K4 trimethylation and MLL1/WDR5 recruitment at the HoxA2 gene. Upon retinoic acid-induced transcriptional activation of HoxA2 in a cell model of neuronal differentiation, PRMT6 recruitment and H3 R2 methylation are diminished and H3 K4 trimethylation increases at the gene. Our findings identify PRMT6 as the mammalian methyltransferase for H3 R2 and establish the enzyme as a crucial negative regulator of H3 K4 trimethylation and transcriptional activation.

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ING4 mediates crosstalk between histone H3 K4 trimethylation and H3 acetylation to attenuate cellular transformation.

Project description:Aberrations in chromatin dynamics play a fundamental role in tumorigenesis, yet relatively little is known of the molecular mechanisms linking histone lysine methylation to neoplastic disease. ING4 (Inhibitor of Growth 4) is a native subunit of an HBO1 histone acetyltransferase (HAT) complex and a tumor suppressor protein. Here we show a critical role for specific recognition of histone H3 trimethylated at lysine 4 (H3K4me3) by the ING4 PHD finger in mediating ING4 gene expression and tumor suppressor functions. The interaction between ING4 and H3K4me3 augments HBO1 acetylation activity on H3 tails and drives H3 acetylation at ING4 target promoters. Further, ING4 facilitates apoptosis in response to genotoxic stress and inhibits anchorage-independent cell growth, and these functions depend on ING4 interactions with H3K4me3. Together, our results demonstrate a mechanism for brokering crosstalk between H3K4 methylation and H3 acetylation and reveal a molecular link between chromatin modulation and tumor suppressor mechanisms.

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Targeting Histone Demethylase LSD1 for Treatment of Deficits in Autism Mouse Models

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-01-13 | GSE193405 | GEO

Phospholipase d2 ablation ameliorates Alzheimer's disease-linked synaptic dysfunction and cognitive deficits.

Project description:Growing evidence implicates aberrant lipid signaling in Alzheimer's disease (AD). While phospholipases A2 and C have been recently shown to mediate key actions of amyloid ?-peptide (A?) through a dysregulation of arachidonic acid and phosphatidylinositol-4,5-bisphosphate metabolism, respectively, the role of phospholipase D (PLD) has so far remained elusive. PLD produces phosphatidic acid (PA), a bioactive lipid involved in multiple aspects of cell physiology, including signaling and membrane trafficking processes. Here we show that oligomeric A? enhances PLD activity in cultured neurons and that this stimulatory effect does not occur upon ablation of PLD2 via gene targeting. A? fails to suppress long-term potentiation in PLD2-deficient hippocampal slices, suggesting that PLD2 is required for the synaptotoxic action of this peptide. In vivo PLD activity, as assessed by detection of phosphatidylethanol levels using mass spectrometry (MS) following ethanol injection, is also increased in the brain of a transgenic mouse model of AD (SwAPP). Furthermore, Pld2 ablation rescues memory deficits and confers synaptic protection in SwAPP mice despite a significant A? load. MS-based lipid analysis of Pld2 mutant brains in the presence or absence of the SwAPP transgene unmasks striking crosstalks between different PA species. This lipid analysis shows an exquisite acyl chain specificity and plasticity in the perturbation of PA metabolism. Collectively, our results point to specific molecular species of PA as key modulators of AD pathogenesis and identify PLD2 as a novel potential target for therapeutics.

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