Drosophila melanogaster
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA133947 | ENA |
REPOSITORIES: ENA
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Project description:Tip60 is a key histone acetyltransferase (HAT) enzyme that plays a central role in diverse biological processes critical for general cell function, however the chromatin-mediated cell-type specific developmental pathways that are dependent exclusively upon the HAT activity of Tip60 remain to be explored. Here, we investigate the role of Tip60 HAT activity in transcriptional control during multicellular development, in vivo by examining genome-wide changes in gene expression in a Drosophila model system specifically depleted for endogenous dTip60 HAT function. We show that amino acid residue E431 in the catalytic HAT domain of dTip60 is critical for the acetylation of endogenous histone H4 in our fly model in vivo, and demonstrate that dTip60 HAT activity is essential for multicellular development. Moreover, our results uncover a novel role for Tip60 HAT activity in controlling neuronal specific gene expression profiles essential for nervous system function as well as a central regulatory role for Tip60 HAT function in general metabolism. Drosophila larvae ubiquitously expressing either our dTIP60 HAT specific mutant or an additional copy of wild type dTIP60 were selected along with age-matched wild type controls for RNA extraction. Two samples, each containing a pool of thirty-five staged whole larvae, were collected from each respective genotypic cross, and were used for hybridization on a separate Affymetrix microarray.
2010-11-29 | E-GEOD-25635 | biostudies-arrayexpress
Project description:Tip60 is a key histone acetyltransferase (HAT) enzyme that plays a central role in diverse biological processes critical for general cell function, however the chromatin-mediated cell-type specific developmental pathways that are dependent exclusively upon the HAT activity of Tip60 remain to be explored. Here, we investigate the role of Tip60 HAT activity in transcriptional control during multicellular development, in vivo by examining genome-wide changes in gene expression in a Drosophila model system specifically depleted for endogenous dTip60 HAT function. We show that amino acid residue E431 in the catalytic HAT domain of dTip60 is critical for the acetylation of endogenous histone H4 in our fly model in vivo, and demonstrate that dTip60 HAT activity is essential for multicellular development. Moreover, our results uncover a novel role for Tip60 HAT activity in controlling neuronal specific gene expression profiles essential for nervous system function as well as a central regulatory role for Tip60 HAT function in general metabolism.
2010-11-29 | GSE25635 | GEO
Project description:Background Tip60 (KAT5) is the histone acetyltransferase (HAT) of the mammalian Tip60/NuA4 complex. While Tip60 is important for early mouse development and mouse embryonic stem cell (mESC) pluripotency, the function of Tip60 as reflected in a genome-wide context is not yet well understood. Results Gel filtration of nuclear mESCs extracts indicate incorporation of Tip60 into large molecular complexes and exclude the existence of large quantities of âfreeâ Tip60 within the nuclei of ESCs. Thus, monitoring of Tip60 binding to the genome should reflect the behaviour of Tip60-containing complexes. The genome-wide mapping of Tip60 binding in mESCs by chromatin immunoprecipitation (ChIP) coupled with high-throughput sequencing (ChIP-seq) shows that the Tip60 complex is present at promoter regions of predominantly active genes that are bound by RNA polymerase II (Pol II) and contain the H3K4me3 histone mark. The coactivator HAT complexes, Tip60- and Mof (KAT8)-containing (NSL and MSL), show a global overlap at promoters, whereas distinct binding profiles at enhancers suggest different regulatory functions of each essential HAT complex. Interestingly, Tip60 enrichment peaks at about 200 bp downstream of the transcription start sites suggesting a function for the Tip60 complexes in addition to histone acetylation. The comparison of genome-wide binding profiles of Tip60 and c-Myc, a somatic cell reprogramming factor that binds predominantly to active genes in mESCs, demonstrate that Tip60 and c-Myc co-bind at 50â60 % of their binding sites. We also show that the Tip60 complex binds to a subset of bivalent developmental genes and defines a set of mESC-specific enhancer as well as super-enhancer regions. Conclusions Our study suggests that the Tip60 complex functions as a global transcriptional co-activator at most active Pol II promoters, co-regulates the ESC-specific c-Myc network, important for ESC self-renewal and cell metabolism and acts at a subset of active distal regulatory elements, or super enhancers, in mESCs. Genome- wide binding of Tip60 co-activator complexes
2015-11-06 | E-GEOD-69671 | biostudies-arrayexpress
Project description:Environmental enrichment (EE) conditions have profound beneficial effects for reinstating cognitive ability in neuropathological disorders like Alzheimerâs disease (AD). While EE benefits involve epigenetic gene control mechanisms that comprise histone acetylation, the histone acetyltransferases (HATs) involved remain largely unknown. Here, we examine a role for Tip60 HAT action in mediating activity- dependent beneficial neuroadaptations to EE using the Drosophila CNS mushroom body (MB) as a well-characterized cognition model. We show that flies raised under EE conditions display enhanced MB axonal outgrowth, synapse protein production, histone acetylation induction and transcriptional activation of cognition linked genes when compared to their genotypically identical siblings raised under isolated conditions. Further, these beneficial changes are impaired in both Tip60 HAT mutant flies and APP neurodegenerative flies. While EE conditions provide only slight beneficial neuroadaptive changes in the APP neurodegenerative fly MB, such positive changes are significantly enhanced by increasing MB Tip60 HAT levels. Our results implicate Tip60 as a critical mediator of EE-induced benefits, and provide insight into synergistic behavioral and epigenetic based approaches for treatment of cognitive disorders. EE has been shown to positively impact gene expression profiles in the mouse brain that are enriched in functions such as neuronal structure, synaptic plasticity and neurotransmission. Thus, we asked whether the EE induced beneficial MB structural and synaptic changes we observe are accompanied by neuroadaptive transcriptional benefits in the Drosophila MB, and if so, is Tip60 HAT action required for this process. To address this question, we accessed EE induced beneficial transcriptional changes using microarray. We crossed our UAS-mCD8-GFP;Tip60E431Q flies or control UAS-mCD8-GFP flies to MB GAL4 OK-107 to simultaneously induce Tip60 HAT loss in the MB while tagging MB cells with GFP. Adult progeny were exposed to EE or ISO conditions. After conditioning, the GFP tagged MB Kenyon neurons were FACs purified from conditioned fly brains from each genotype to enrich for detection of an EE induced MB transcriptional response. RNA was isolated from the purified Kenyon MB neurons and transcriptional changes for each genotype were assessed using microarray analysis
2016-01-07 | E-GEOD-76612 | biostudies-arrayexpress
Project description:Environmental enrichment (EE) conditions have profound beneficial effects for reinstating cognitive ability in neuropathological disorders like Alzheimer’s disease (AD). While EE benefits involve epigenetic gene control mechanisms that comprise histone acetylation, the histone acetyltransferases (HATs) involved remain largely unknown. Here, we examine a role for Tip60 HAT action in mediating activity- dependent beneficial neuroadaptations to EE using the Drosophila CNS mushroom body (MB) as a well-characterized cognition model. We show that flies raised under EE conditions display enhanced MB axonal outgrowth, synapse protein production, histone acetylation induction and transcriptional activation of cognition linked genes when compared to their genotypically identical siblings raised under isolated conditions. Further, these beneficial changes are impaired in both Tip60 HAT mutant flies and APP neurodegenerative flies. While EE conditions provide only slight beneficial neuroadaptive changes in the APP neurodegenerative fly MB, such positive changes are significantly enhanced by increasing MB Tip60 HAT levels. Our results implicate Tip60 as a critical mediator of EE-induced benefits, and provide insight into synergistic behavioral and epigenetic based approaches for treatment of cognitive disorders. EE has been shown to positively impact gene expression profiles in the mouse brain that are enriched in functions such as neuronal structure, synaptic plasticity and neurotransmission. Thus, we asked whether the EE induced beneficial MB structural and synaptic changes we observe are accompanied by neuroadaptive transcriptional benefits in the Drosophila MB, and if so, is Tip60 HAT action required for this process. To address this question, we accessed EE induced beneficial transcriptional changes using microarray.
2016-01-07 | GSE76612 | GEO
Project description:The histone lysine acetyltransferase TIP60 is the main enzyme that catalyzes histone H4 acetylation in cells. Domains on TIP60 regulate its enzymatic activity from different aspects. Here we use a CRISPR-Cas9 tiling screen to scan for essential domains on TIP60 protein and found that the Tudor-knot domain is essential for cell survival and intercellular H4 acetylation. We performed in-vitro biochemical assays and demonstrated Tudor-knot domain is not a histone reader. And deficiency of the Tudor-knot domain has mild effects on TIP60 intracellular localization, as well as the TIP60 complex’s constitution. But Tudor-knot deficiency significantly reduces TIP60 HAT activity both in vivo and in vitro. By comparing the catalytic efficiency of nucleosome substrate and histone octamer substrate, as well as TIP60 protein alone or TIP60 complex, we found the nucleosomal structure and other TIP60 complex components are required for Tudor-knot relative HAT activity regulation. We propose that the Tudor-knot domain function to increase nucleosome accessibility. Finally, we show that the Tudor-knot domain is required for TIP60-dependent transcription regulation. Altogether, our study reveals a mechanism that the Tudor-knot domain that regulates TIP60-dependent transcription through the regulation of TIP60 substrate catalytic efficiency.
2023-12-24 | GSE245116 | GEO
Project description:The histone lysine acetyltransferase TIP60 is the main enzyme that catalyzes histone H4 acetylation in cells. Domains on TIP60 regulate its enzymatic activity from different aspects. Here we use a CRISPR-Cas9 tiling screen to scan for essential domains on TIP60 protein and found that the Tudor-knot domain is essential for cell survival and intercellular H4 acetylation. We performed in-vitro biochemical assays and demonstrated Tudor-knot domain is not a histone reader. And deficiency of the Tudor-knot domain has mild effects on TIP60 intracellular localization, as well as the TIP60 complex’s constitution. But Tudor-knot deficiency significantly reduces TIP60 HAT activity both in vivo and in vitro. By comparing the catalytic efficiency of nucleosome substrate and histone octamer substrate, as well as TIP60 protein alone or TIP60 complex, we found the nucleosomal structure and other TIP60 complex components are required for Tudor-knot relative HAT activity regulation. We propose that the Tudor-knot domain function to increase nucleosome accessibility. Finally, we show that the Tudor-knot domain is required for TIP60-dependent transcription regulation. Altogether, our study reveals a mechanism that the Tudor-knot domain that regulates TIP60-dependent transcription through the regulation of TIP60 substrate catalytic efficiency.
2023-12-24 | GSE245115 | GEO
Project description:Tip60 HAT action mediates environmental enrichment induced cognitive restoration
| PRJNA308139 | ENA
Project description:Background Tip60 (KAT5) is the histone acetyltransferase (HAT) of the mammalian Tip60/NuA4 complex. While Tip60 is important for early mouse development and mouse embryonic stem cell (mESC) pluripotency, the function of Tip60 as reflected in a genome-wide context is not yet well understood. Results Gel filtration of nuclear mESCs extracts indicate incorporation of Tip60 into large molecular complexes and exclude the existence of large quantities of “free” Tip60 within the nuclei of ESCs. Thus, monitoring of Tip60 binding to the genome should reflect the behaviour of Tip60-containing complexes. The genome-wide mapping of Tip60 binding in mESCs by chromatin immunoprecipitation (ChIP) coupled with high-throughput sequencing (ChIP-seq) shows that the Tip60 complex is present at promoter regions of predominantly active genes that are bound by RNA polymerase II (Pol II) and contain the H3K4me3 histone mark. The coactivator HAT complexes, Tip60- and Mof (KAT8)-containing (NSL and MSL), show a global overlap at promoters, whereas distinct binding profiles at enhancers suggest different regulatory functions of each essential HAT complex. Interestingly, Tip60 enrichment peaks at about 200 bp downstream of the transcription start sites suggesting a function for the Tip60 complexes in addition to histone acetylation. The comparison of genome-wide binding profiles of Tip60 and c-Myc, a somatic cell reprogramming factor that binds predominantly to active genes in mESCs, demonstrate that Tip60 and c-Myc co-bind at 50–60 % of their binding sites. We also show that the Tip60 complex binds to a subset of bivalent developmental genes and defines a set of mESC-specific enhancer as well as super-enhancer regions. Conclusions Our study suggests that the Tip60 complex functions as a global transcriptional co-activator at most active Pol II promoters, co-regulates the ESC-specific c-Myc network, important for ESC self-renewal and cell metabolism and acts at a subset of active distal regulatory elements, or super enhancers, in mESCs.
2015-11-06 | GSE69671 | GEO
Project description:Histone acetyltransferases (HATs) and deacetylases (HDACs) function antagonistically to control histone acetylation. As acetylation is a histone mark for active transcription, HATs have been associated with active and HDACs with inactive genes. We describe here genome-wide mapping of HATs and HDACs binding on chromatin and find that both are found at active genes with acetylated histones. Our data provide evidence that HATs and HDACs are both targeted to transcribed regions of active genes by phosphorylated RNA Pol II. Furthermore, the majority of HDACs in the human genome function to reset chromatin by removing acetylation at active genes. Inactive genes that are primed by MLL-mediated histone H3K4 methylation are subject to a dynamic cycle of acetylation and deacetylation by transient HAT/HDAC binding, preventing Pol II from binding to these genes but poising them for future activation. Silent genes without any H3K4 methylation signal show no evidence of being bound by HDACs. high throughput sequencing: genome-wide analysis of 5 HATs, 4 HDACs in human CD4+ cells, Tip60 and HDAC6 in activated CD4 cells, genome-wide analysis of 2 histone acetylations and RNA Polymerase II after HDAC inhibitor treatment in CD4, histone modification with WDR5 knock-down and HDAC inhibitor treatment in HeLa cells expression profiling: Global change in gene expression in human CD4+ T cells after HDAC inhibitor treatment for 2hours and 12 hours. (9 samples in total)
2009-08-20 | E-GEOD-15735 | biostudies-arrayexpress