The Tip60 acetylome is a hallmark of the proliferative state in Drosophila
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PROVIDER: PRJNA1287565 | ENA |
REPOSITORIES: ENA
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Project description:The acetyltransferase KAT5/Tip60 is an epigenetic regulator of transcription and the DNA damage response. In Drosophila, Tip60 acetylates histones as part of the Dom-A complex, but it is unclear whether it has other substrates. In this work, we comprehensively studied the functions of Tip60 in a Drosophila proliferative cell model. Depletion of Tip60 arrests the cell cycle, but remaining viable cells resist mutagenic irradiation. The impaired proliferation is explained by reduced expression of critical cell cycle genes. Tip60 binds their transcription start sites and Tip60-dependent acetylation of the histone variant H2A.V correlates with transcription activity. A potentially synergistic pathway for cell cycle regulation involves the acetylation of proteins other than histones. The Tip60-dependent nuclear acetylome contains hundreds of proteins, many of which are involved in diverse aspects of cell growth and division, including replication, mitosis, gene expression, chromatin organization and ribosome biogenesis. We hypothesize that Tip60 coordinates the proliferative state through histone and non-histone effectors. Reversible acetylation of diverse effector proteins bears potential for fine-tuning energy-intensive processes in response to stresses or nutritional shortcomings. Our study portrays the DOM-A/TIP60 complex as a general promoter of cell proliferation.
2025-07-16 | GSE301786 | GEO
Project description:The acetyltransferase KAT5/Tip60 is a key epigenetic regulator of transcription and the DNA damage response. In Drosophila, Tip60 functions within the DOM-A complex to acetylate histones, but its broader substrate repertoire and cellular roles remain incompletely defined. Here, we comprehensively investigated the functions of Tip60 in a proliferative Drosophila cell model. Tip60 depletion caused cell cycle arrest, yet surviving cells exhibited resistance to mutagenic irradiation. This impaired proliferation was accompanied by reduced expression of critical cell cycle regulators, with Tip60 binding at their transcription start sites and Tip60-dependent acetylation of the histone variant H2A.V correlating with transcriptional activation. Beyond chromatin, Tip60 was found to acetylate a wide range of nuclear proteins involved in replication, mitosis, gene expression, chromatin organization, and ribosome biogenesis. These findings suggest that Tip60 coordinates the proliferative state through the combined regulation of histone and non-histone substrates. We propose that reversible acetylation of diverse effector proteins provides a mechanism for dynamically adjusting growth-related processes in response to cellular stress or nutrient availability. Collectively, this work identifies the DOM-A/Tip60 complex as a general promoter of cell proliferation.
2025-07-16 | PXD066107 | Pride
Project description:Methylation state of latent and proliferative metastatic tumor cells
| PRJNA913188 | ENA
Project description:The Tip60 (also known as Kat5) lysine acetyltransferase functions broadly as a transcriptional co-activator that acetylates histones. In contrast, Tip60 functions in embryonic stem cells (ESCs) both to silence genes that promote differentiation and to activate genes required for proliferation. The mechanism by which Tip60 functions as a repressor is unknown. Here we show that the class II histone deacetylase Hdac6 co-purifies with Tip60-p400 complex from ESCs and is necessary for complete silencing of most differentiation genes targeted by Tip60. In contrast to differentiated cells, where Hdac6 is mainly cytoplasmic and does not interact with Tip60, Hdac6 is largely nuclear in ESCs and neural stem cells (NSCs) and interacts with Tip60-p400 in both cell types. Hdac6 is enriched at promoters bound by Tip60-p400 in ESCs, but while Tip60 binds on both sides of transcription start sites (TSSs), Hdac6 binding overlaps with only the downstream Tip60 peak. Surprisingly, Hdac6 does not deacetylate histones at these sites, but rather is required for Tip60 binding. These data suggest that nuclear exclusion of Hdac6 during differentiation plays a major role in modulation of Tip60-p400 function. We determined the genome-wide localization of Tip60 and Hdac6 in mouse ES cells, and examined genomic binding profiles of Tip60 and Hdac6 upon indicated knockdown by ChIP-seq. We examined genomic binding profiles of p400 upon indicated knockdown by ChIP-seq.
2013-11-20 | E-GEOD-42209 | biostudies-arrayexpress
Project description:Genome-wide mapping of TIP60 complex subunits in K562 cells. The objectives of this study are to describe TIP60 genome wide localization, confirm MBTD1 co-localization with already known unique subunits and observe the impact of MBTD1 on TIP60 complex targeting to chromatin. The TIP60 acetyltransferase complex is a key regulator of genome expression and stability. Here, we identified MBTD1 as a new stable subunit of the complex and revealed interesting insights about TIP60 function during the repair of DNA double strand breaks. MBTD1 binds H4K20me1/2, helping TIP60 association to specific promoters but also the DNA repair process by homologous recombination. While pro-end joining factor 53BP1 engages chromatin through simultaneous binding of H4K20me2 and H2AK15ub, TIP60 regulates the resolution of 53BP1 foci after DNA damage through a related bivalent mechanism. MBTD1 competes with 53BP1 for the H4K20me2 mark, affecting its retention at the break cooperatively with H4 acetylation by TIP60. In addition, we show that H2AK15ub deposition by RNF168 inhibits chromatin acetylation by TIP60, whereas H2AK15 can also be acetylated by TIP60 in vivo, therefore blocking its ubiquitylation. Altogether, these results uncover an intricate mechanism orchestrated by the TIP60 complex to regulate 53BP1-dependent repair pathway selection, through incompatible bivalent binding/action on chromatin.
2016-04-30 | GSE69645 | GEO
Project description:The Tip60 (also known as Kat5) lysine acetyltransferase functions broadly as a transcriptional co-activator that acetylates histones. In contrast, Tip60 functions in embryonic stem cells (ESCs) both to silence genes that promote differentiation and to activate genes required for proliferation. The mechanism by which Tip60 functions as a repressor is unknown. Here we show that the class II histone deacetylase Hdac6 co-purifies with Tip60-p400 complex from ESCs and is necessary for complete silencing of most differentiation genes targeted by Tip60. In contrast to differentiated cells, where Hdac6 is mainly cytoplasmic and does not interact with Tip60, Hdac6 is largely nuclear in ESCs and neural stem cells (NSCs) and interacts with Tip60-p400 in both cell types. Hdac6 is enriched at promoters bound by Tip60-p400 in ESCs, but while Tip60 binds on both sides of transcription start sites (TSSs), Hdac6 binding overlaps with only the downstream Tip60 peak. Surprisingly, Hdac6 does not deacetylate histones at these sites, but rather is required for Tip60 binding. These data suggest that nuclear exclusion of Hdac6 during differentiation plays a major role in modulation of Tip60-p400 function.
2013-11-20 | GSE42209 | GEO
Project description:USP7, a dominant DUB activity in 3T3-L1 adipocytes and in mouse adipose tissue, increases Tip60 protein levels, and deubiquitinates Tip60 both in intact cells and in vitro. Treatment with a pan deubiquitinase (DUB) inhibitor, or knockdown of USP7, decreases adipogenesis. Transcriptome analysis reveals a common set of cell cycle genes to be co-regulated by both Tip60 and USP7. Knock down of either factor results in impaired mitotic clonal expansion, an early step in adipogenesis. These results therefore reveal deubiquitination of a transcriptional coregulator to be a key mechanism in the regulation of early adipogenesis Mature 3T3-L1 adipocytes were subjected to RNAi-mediated knock down with control(C), USP7(U)- or Tip60(T)-specific oligonucleotides. For this, 4 replicates of differentiated 3T3-L1 cells were transfected with Amaxa technology. Two days after transfection cells were washed twice with PBS twice and lysed in 0.5ml Trizol (Invitrogen). mRNA expression of Tip60 and USP7 was assessed by qRT-PCR. Amplified cRNA samples were labeled with either cy3 or cy5 and put on microarray together with and oppositely labeled common reference sample consisting of cRNA derived from undifferentiated 3T3-L1 cells.
2013-08-28 | E-GEOD-28587 | biostudies-arrayexpress
Project description:Alternative splicing of RNA transcripts can result in a multitude of variations from the genome. Since splicing can occur co-transcriptionally, chromatin structure has been reported to affect the choice of a splice site. TIP60 is a haploinsufficient tumor suppressor gene that is frequently downregulated in cancers. Since TIP60 is a writer of histone and non-histone modifications, we investigated TIP60’s role in modulating alternative splicing. RNA sequencing was performed in TIP60-depleted MCF10A cells and with cells rescued with wild-type or catalytically inactive TIP60. The majority of the differential splicing events were skipped exon events, including exon 25 skipping event of ITGA6. To identify the splicing factor that regulates this event, a siRNA screen of 77 splicing factors was employed. TIP60 depletion results in an increase in the ITGA6 isoform that lacks exon 25 and the siRNA screen identified ESRP2 to regulate splicing of ITGA6 exon 25. This study suggests that alternative splicing of ITGA6 exon 25 is regulated by the TIP60-ESRP2 axis.
2023-06-19 | GSE152863 | GEO
Project description:Lysine 2-hydroxyisobutyrylation (Khib) is an evolutionary conserved and widespread protein posttranslational modification (PTM) that has diverse cellular functions. Recently, it has been demonstrated that Khib can be regulated by p300 and Tip60. Although the specific Khib substrates mediated by p300 has been revealed, how Tip60 regulates diverse cellular processes through the Khib pathway and the different roles between Tip60 and p300 towards regulating Khib remains largely unknown, which hinders our understanding of the mechanisms by which this modification exerts its biological functions. Here we report the first Khib proteome mediated by Tip60. A total of 2999 unique Khib sites on 956 proteins were identified. Among them, 397 Khib sites from 322 proteins presented only in Tip60 overexpressing cells and 10 Khib sites increased greater than 2-fold in response of Tip60 overexpression, indicating that Tip60 significantly affected global Khib . Surprisingly, only 5 of the 407 Tip60-targeted Khib sites overlapping with the 149 known p300-targeted Khib sites, indicating that Tip60 and p300 have different substrate preference for Khib. In addition, the Khib substrates regulated by Tip60 are deeply involved in processes such as mRNA translation and protein co-folding, and some are associated with diseases such as Parkinson. Together, this study reveals the Khib substrates in response to Tip60, which elucidates the role of Tip60 in regulating various cellular processes through Khib pathway, and provides new insights into functional mechanism of Tip60.
2022-02-22 | PXD029297 | Pride