Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A Genome-wide CRISPR-Based Screen Identifies KAT7 as a Senescence Driver

ABSTRACT: Understanding the genetic and epigenetic bases of cellular senescence is instrumental to aging intervention. We performed genome-wide CRISPR/Cas9-based screens in two human mesenchymal precursor cell (hMPC) models of progeroid syndromes and identified hundreds of genes whose deficiency alleviated cellular senescence. Among them, KAT7, a histone acetyltransferase, ranked as a top hit in both models. Inactivation of KAT7 decreased H3 lysine 14 acetylation (H3K14ac), repressed p15INK4b transcription, and rejuvenated both physiologically and pathologically aged cells. Moreover, lentiviral vectors encoding Cas9/sg-Kat7 alleviated liver senescence and extended healthspan and lifespan of mice. Our findings demonstrate that CRISPR/Cas9-based genetic screening is a robust method for systematically uncovering unknown senescence genes, of which KAT7 may represent a new therapeutic target for aging intervention.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE124197 | GEO | 2020/10/09

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

A Genome-wide CRISPR-Based Screen Identifies KAT7 as a Senescence Driver

Project description:A Genome-wide CRISPR-Based Screen Identifies KAT7 as a Senescence Driver

| PRJNA510979 | ENA

Stem cell plasticity, acetylation of H3K14 and de novo gene activation rely on KAT7

Project description:In the conventional model of transcriptional activation, transcription factors bind to response elements and recruit co-factors, including histone acetyltransferases. Contrary to this model, we show that the histone acetyltransferase KAT7 (HBO1/MYST2) is required genome-wide for histone H3 lysine 14 acetylation (H3K14ac). Examining neural stem cells, we found that KAT7 and H3K14ac were present not only at transcribed genes, but also at inactive genes, intergenic regions and in heterochromatin. KAT7 and H3K14ac were not required for the continued transcription of genes that were actively transcribed at the time of loss of KAT7, but indispensable for the activation of repressed genes. The absence of KAT7 abrogated neural stem cell plasticity, diverse differentiation pathways and cerebral cortex development. Reexpression of KAT7 restored stem cell developmental potential. Overexpression of KAT7 enhanced neuron and oligodendrocyte differentiation. Our data suggest that KAT7 prepares chromatin for transcriptional activation and is a prerequisite for gene activation.

2022-12-09 | GSE220602 | GEO

ESC-sEVs rejuvenate aging hippocampal NSCs by transferring SMADs to regulate the MYT1-Egln3-Sirt1 axis

Project description:Tissue stem cell senescence leads to stem cell exhaustion, which results in tissue homeostasis imbalance and a decline in regeneration capacity. However, whether neural stem cells (NSCs) senescence occurs and causes neurogenesis reduction during aging is unknown. In this study, mice at different ages were used to detect age-related hippocampal NSCs (H-NSCs) senescence, as well as the function and mechanism of embryonic stem cells derived small extracellular vesicles (ESC-sEVs) in rejuvenating H-NSCs senescence. We found a progressive cognitive impairment, as well as age-related H-NSCs senescence, in mice. ESC-sEVs treatment significantly alleviated H-NSCs senescence, recovered compromised self-renewal and neurogenesis capacities, and reversed cognitive impairment. Transcriptome analysis revealed that Myelin transcription factor 1 (MYT1) is downregulated in senescent H-NSCs but upregulated by ESC-sEV treatment. In addition, knockdown of MYT1 in young H-NSCs accelerated age-related phenotypes and impaired proliferation and differentiation capacities. Mechanistically, ESC-sEVs rejuvenated senescent H-NSCs partly by transferring SMAD4 and SMAD5 to activate MYT1, which downregulated Egln3, followed by activation of HIF2α, NAMPT, and Sirt1 successively. Taken together, our results indicated that H-NSCs senescence caused cellular exhaustion, neurogenesis reduction and cognitive impairment during aging, which can be reversed by ESC-sEVs. Thus, ESC-sEVs may be promising therapeutic candidates for age-related diseases.

2023-09-09 | GSE158000 | GEO

RNA-seq of murine proliferating neural stem and progenitor cells from Kat7-deleted mouse fetuses

Project description:Tissue-specific deletion of the gene encoding the histone acetyltransferase Kat7 (Hbo1) in the developing mouse central nervous system using cre-recombinase expression driven by regulatory sequences of the nestin locus (NesCre transgene) resulted in defective cerebral cortex development, a complete failure of neural stem cells to give rise to neurons and oligodendrocytes during in vitro differentiation, and a failure to express the neuronal differentiation program. Proliferating neural stem and progenitor cells (NPSCs) were isolated from Kat7-deleted and Kat7-intact 14.5 day embryonic mouse fetuses.

2022-12-09 | GSE220498 | GEO

Chemical Screen Identifies a Geroprotective Role of Quercetin in Premature and Physiological Aging

Project description:Aging increases the vulnerability to various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a nature product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate targets were identified and quercetin was further investigated due to its leading effects. Mechanistic studies revealed that in WS hMSCs, quercetin alleviated senescence via the enhancement of cell proliferation and the restoration and differentiation of heterochromatin architecture. RNA-seq analysis uncovered that quercetin and Vitamin C exerted geroprotective effects through different mechanisms. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS), physiological-aging and replicative-senescent hMSCs. More importantly, quercetin significantly improved the exercise endurance of old C57Bl/6 mice. Taken together, our study identifies quercetin as a geroprotective agent against premature and physiological aging, providing a novel therapeutic intervention for treating premature aging and promoting healthy aging.

2018-06-23 | GSE116166 | GEO

A minimal DNA sequence within the ARF promoter represses p16INK4A expression via long-range chromatin interaction [Cut&Run ChiP-seq]

Project description:Loss of function of CDKN2A/B, also known as INK4/ARF [encoding for p16INK4A, p15INK4B, and p14ARF (mouse p19Arf)]), confers susceptibility to cancers, whereas its up-regulation during organismal aging provokes cellular senescence and tissue degenerative disorders. To better understand molecular regulation of the locus, we knocked P2A-mCherry into the C-terminus of p16INK4A, and this construct faithfully recapitulated the endogenous transcription. Using this reporter cell line, we performed a noncoding tiling pooled screening targeting open chromatin regions spanning the approximately 500-kb region in the topological associated domain that includes p16INK4A. In both Cas9- and dCas9-KRAB–mediated screenings, we identified a 42-bp DNA sequence within exon 1β of the ARF gene, as the repressive element controlling p16INK4A expression. Chromatin conformation capture indicated that inactivating this element abolished the physical interaction between p15INK4B and ARF, thereby abolishing p16INK4A repression. This study has revealed a new mechanism of transcriptional regulation of p16INK4A by long-range chromatin interaction.

2019-12-17 | GSE125841 | GEO

A minimal DNA sequence within the ARF promoter represses p16INK4A expression via long-range chromatin interaction [Capture-C]

2019-12-17 | GSE125666 | GEO

KAT7 maintains myeloid leukemogenesis recruits BRD4 to the promoters of target loci to maintain then MLL-AF9 transcriptional programme

Project description:Here we investigate the essentiality of lysine acetyltransferase KAT7 in AMLs driven by the MLL-X fusions. We find that KAT7 activity is required for the recruitment of the MLL-fusion associated adaptor proteins such as BRD4 to gene promoters, which are critical for the maintenance of the MLL-AF9 transcriptional programme. Our findings propose that KAT7 is a plausible therapeutic target for this poor prognosis subtype of AML.

2020-07-27 | GSE133516 | GEO

Chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) detection of histone H3 lysine 14 acetylation (H3K14ac) and KAT7 (HBO1) in E14.5 mouse neural stem and progenitor cells (NSPCs)

Project description:Tissue specific deletion of the gene encoding the histone acetyltransferase KAT7 (HBO1) in the developing mouse central nervous system using cre-recombinase expression driven by regulatory sequences of the nestin locus (NesCre transgene) resulted in defective cerebral cortex development, a complete failure of neural stem cells to give rise to neurons and oligodendrocytes during in vitro differentiation and a failure to express the neuronal differentiation program. KAT7 genome occupancy and histone H3 lysine 14 acetylation (H3K14ac) levels were assessed by ChIP-seq in proliferating Kat7 deleted vs. Kat7 intact neural stem and progenitor cells (NSPCs). KAT7 and H3K14ac were completely absent in the Kat7 deleted cells. IN KAT7 intact cells, KAT7 occupancy levels and H3K14ac levels within the body of genes correlated strongly and positively. Both were higher in genes that were expressed strongly than in genes with lower or no expression. However, KAT7 and H3K14ac were present in all genes including silent genes and in all other regions of the genome, including intergenic regions and regions decorated with histone H3 lysine 9 trimethylation (H3K9me3), an indicator of constitutive heterochromatin.

2022-11-30 | GSE216459 | GEO

RNA-seq and ATAC-seq profiling of thymic epithelial cells from wildtype and Kat7 knockout mice

Project description:The autoimmune regulator, AIRE, induces the transcription of thousands of peripheral tissue genes (PTGs) in thymic epithelial cells (TECs) to mediate immunological tolerance. The chromatin state required for optimal AIRE function in TECs and how this state is induced remains unclear. Using RNA-seq and ATAC-seq, we tested the role of the histone acetyltransferase, KAT7 (also known as HBO1 or MYST2), which is essential for acetylation of histone 3 lysine 14 (H3K14), in TEC differentiation, AIRE-mediated PTG expression and thymic tolerance. We find that KAT7 is required for optimal expansion of medullary TEC and has a major role in the expression of AIRE-dependent PTGs, associated with enhanced chromatin accessibility at these gene loci in TECs. Mice with TEC-specific Kat7 deletion develop organ-specific autoimmunity with features resembling those observed in Aire-deficient mice. These findings highlight critical roles for KAT7-mediated acetylation in promoting a chromatin state at PTG loci that enables AIRE function and the establishment of immunological tolerance.

2021-12-21 | GSE188871 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data