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KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3 [RNA-seq]

ABSTRACT: KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3 [RNA-seq]

PROVIDER: PRJNA1085118 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28254702_1.fastq.gz	Fastqsanger.gz
	SRR28254702_2.fastq.gz	Fastqsanger.gz
	SRR28254703_1.fastq.gz	Fastqsanger.gz
	SRR28254703_2.fastq.gz	Fastqsanger.gz
	SRR28254704_1.fastq.gz	Fastqsanger.gz

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KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3 [RNA-seq]

Project description:Intellectual disability (ID) affects ~2% of the population and ID-associated genes are enriched for epigenetic factors, including those encoding the largest family of histone lysine acetyltransferases (KAT5-KAT8). Among them is KAT6A, whose mutations cause KAT6A Syndrome, with ID as a common clinical feature. However, the underlying molecular mechanism remains unknown. Here, we find that KAT6A deficiency impairs synaptic structure and plasticity in hippocampal CA3, but not in CA1 region, resulting in memory deficits in mice. We further identify a CA3-enriched gene Rspo2, encoding Wnt activator R-spondin 2, as a key transcriptional target of KAT6A. Importantly, deletion of Rspo2 in excitatory neurons impairs memory formation, and restoring RSPO2 expression in CA3 rescues the deficits in Wnt signaling and learning-associated behaviors in Kat6a mutant mice. Collectively, our results demonstrate that KAT6A-RSPO2-Wnt signaling plays a critical role in regulating hippocampal CA3 synaptic plasticity and cognitive function, providing potential therapeutic targets for KAT6A Syndrome and related neurodevelopmental diseases.

2024-03-12 | GSE261058 | GEO

KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3 [snRNA-seq]

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KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3 [snRNA-seq]

Project description:KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3 [snRNA-seq]

| PRJNA1085465 | ENA

Gene expression profiling in differential cognitive outcomes in aging: CA3

Project description:Functional alterations in medial temporal lobe structures, particularly the hippocampus, are central to age-related deficits in episodic memory. Research in aging laboratory animals has characterized physiological and cellular alterations in the hippocampus that occur in association with the presence and severity of such cognitive impairment. The current study compares alterations across hippocampal subregions by gene expression profiling in a rat model that closely mirrors individual differences in neurocognitive features of aging humans across a spectrum of outcomes, including both impaired memory and preserved function. Using mRNA profiling of the CA1, CA3 and dentate gyrus subregions, we have distinguished between gene groups and pathways related to chronological age and those specifically associated with impaired or preserved cognitive ability in aged rats. We confirmed earlier reported changes in gene groups related to inflammation and oxidative stress in multiple subregions and found these to be more associated with chronological age than cognitive function per se. The CA3 profile was best able to segregate aged impaired, aged unimpaired and young subject groups from each other. Characterization of gene changes that distinguished preserved from impaired function among the aged animals found altered expression of synaptic plasticity and neurodegenerative disease-related genes. Together these gene changes suggest recruitment of adaptive mechanisms that mediate synaptic plasticity to maintain function and structural integrity in aged unimpaired rats that does not occur in aged impaired animals.

2009-11-01 | GSE14724 | GEO

Hippocampal CA3 Transcriptional Modules Associated with Granule Cell Alterations and Cognitive Impairment in Refractory Mesial Temporal Lobe Epilepsy Patients

Project description:In about a third of the patients with epilepsy the seizures are not drug-controlled. The current limitation of the antiepileptic drug therapy derives from an insufficient understanding of epilepsy pathophysiology. In order to overcome this situation, it is necessary to consider epilepsy as a disturbed network of interactions, instead of just looking for changes in single molecular components. Here, we studied CA3 transcriptional signatures and dentate gyrus histopathologic alterations in hippocampal explants surgically obtained from 57 RMTLE patients submitted to corticoamygdalohippocampectomy. By adopting a systems biology approach, integrating clinical, histopathological and transcriptomic data trough weighted gene co-expression network analysis, we were able to identify transcriptional modules highly correlated with age of disease onset, cognitive dysfunctions, and granule cell alterations.

2021-05-19 | GSE163296 | GEO

The histone acetyltransferase KAT6A is recruited to unmethylated CpG islands via a DNA-binding winged helix domainThe histone acetyltransferase KAT6A is recruited to unmethylated CpG islands via a DNA-binding winged helix domain

Project description:The lysine acetyltransferase KAT6A (MOZ, MYST3) belongs to the MYST family of chromatin regulators, facilitating histone acetylation. Dysregulation of KAT6A has been implicated in developmental syndromes and the onset of acute myeloid leukemia (AML). Previous work suggests that KAT6A is recruited to its genomic targets by a combinatorial function of histone binding PHD fingers, transcription factors and chromatin binding interaction partners. Here, we demonstrated that a winged helix domain at the N-terminus of KAT6A specifically interacts with unmethylated CpG motifs. This DNA binding function leads to the association of KAT6A to unmethylated CpG islands (CGIs) genome wide. Mutation of the essential amino acids completely abrogates the enrichment of KAT6A at CGIs. Overexpression of a KAT6A WH1 mutant has a dominant negative effect on H3K9 histone acetylation, which is comparable to the effects upon overexpression of a KAT6A HAT domain mutant. Taken together, our work revealed a previously unrecognized chromatin recruitment mechanism of KAT6A, offering a new perspective on the role of KAT6A in gene regulation and human diseases

2023-01-14 | PXD034833 | Pride

Hippocampal subfield transcriptomic profiles: Regional vulnerability to age and cognitive impairment

Project description:The current study employed next-generation RNA sequencing to examine gene expression related to brain aging and cognitive decline. Young and aged rats were trained on a spatial episodic memory task. Hippocampal regions CA1, CA3 and the dentate gyrus (DG) were isolated. Poly-A mRNA was examined using two different platforms, Illumina and Ion Proton. The Illumina platform was used to generate lists of genes that were differentially expressed across regions, ages, and in association with cognitive function. The gene lists were then retested using the Ion Proton platform. The results describe regional differences in gene expression and point to regional differences in vulnerability to aging. Aging was associated with increased expression of immune response related genes, particularly in the dentate gyrus. Finally, for the memory task used, impaired performance of aged animals was linked to the regulation of Ca2+ and synaptic function in region CA1.

2017-12-08 | GSE97608 | GEO

Time-dependent response of hippocampal CA1 and CA3 to oxidative stress

Project description:Mechanistic study on the differential responses of the two hippocampal adjoining regions, i.e., CA1 and CA3, to elevated oxidative stress. Keywords: Time course stress response study

2008-01-08 | GSE6693 | GEO

Efficient generation of human CA3 neurons and modeling hippocampal neuronal connectivity in vitro (bulk)

Project description:Despite widespread interest in using human stem cells in neurological disease modeling, a suitable model system to study human neuronal connectivity is lacking. Here, we report a protocol for efficient differentiation of hippocampal pyramidal neurons and an in vitro model for hippocampal neuronal connectivity. We developed an embryonic stem cell (ESC)- and induced pluripotent stem cell (iPSC)-based protocol to differentiate human CA3 pyramidal neurons from patterned hippocampal neural progenitor cells (NPCs). This differentiation induces a comprehensive patterning and generates multiple CA3 neuronal subtypes. The differentiated CA3 neurons are functionally active and readily form neuronal connection with dentate granule (DG) neurons in vitro, recapitulating the synaptic connectivity within the hippocampus. When we applied this neuronal co-culture approach to study connectivity in schizophrenia, we found deficits in spontaneous activity in patient iPSC derived DG–CA3 co-culture by multi-electrode array recording. In addition, both multi-electrode array recording and whole cell patch clamp electrophysiology revealed a reduction in spontaneous and evoked neuronal activity in CA3 neurons derived from schizophrenia patients. Altogether these results underscore the relevance of this new model in studying diseases with hippocampal vulnerability.

2018-05-02 | GSE111977 | GEO

Expression data of hippocampal CA3 from Adora1 knockout and wild type mice

Project description:Purpose: The goals of this study are to analyze the mRNAs expression in hippocampal CA3 after Adora1 knockout by High-throughput sequencing. Methods: The brain was dissected and followed by 20 μm cryosection onto 20 glass slides. The hippocampus CA3 was isolated from brain slides by using laser capture microdissection. Then the samples were stored on dry ice until RNA extraction by Trizol. The RNAseq was conducted by using Illumina HiSeq2000 platform. Results: By performing RNA sequencing on RNAs isolated from the hippocampus CA3 neurons of AKO and C57 mice at 3-month-old. We found that 51 mRNAs were upregulated, whereas 77 mRNAs were downregulated in AKO mice. Conclusion:We deciphered the underlying neuroprotective mechanisms of A1R knockdown in AD mouse models. By employing the RNA-seq technique, we compared the alterations in gene expression in the hippocampus between AKO and wild-type mice.

2022-01-20 | GSE193826 | GEO

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