Tudor-knot domain mutation in KAT8/MOF impede nucleosome interaction and histone acetylation [ChIP-Seq]
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ABSTRACT:
PROVIDER: PRJNA1026613 | ENA |
REPOSITORIES: ENA
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Project description:KAT8 is a lysine acetyltransferase and is involved in multiple important biological processes including cancer. The well-known function of KAT8 is catalyzing acetylation on histone H4, which regulates gene expression and chromatin decompaction. Besides catalytic HAT domain, the function of Tudor-knot domain of KAT8 remains largely unclear. Here, we report a novel function of Tudor-knot domain in facilitates histone acetyltransferase activity on H4K16ac. One hot-spot cancer mutation on Tudor-knot domain of KAT8 inhibits its interaction with nucleosome and reduces H4K16ac level both in vitro and in cells without altering the chromatin occupancy. Interestingly, this Tudor-knot mutation does not influence acetylation activity of KAT8 on p53, a non-histone substrate, suggests the important function of KAT8 Tudor-knot domain in the substrate specific catalytic regulation.
2023-12-24 | GSE245008 | GEO
Project description:KAT8 is a lysine acetyltransferase and is involved in multiple important biological processes including cancer. The well-known function of KAT8 is catalyzing acetylation on histone H4, which regulates gene expression and chromatin decompaction. Besides catalytic HAT domain, the function of Tudor-knot domain of KAT8 remains largely unclear. Here, we report a novel function of Tudor-knot domain in facilitates histone acetyltransferase activity on H4K16ac. One hot-spot cancer mutation on Tudor-knot domain of KAT8 inhibits its interaction with nucleosome and reduces H4K16ac level both in vitro and in cells without altering the chromatin occupancy. Interestingly, this Tudor-knot mutation does not influence acetylation activity of KAT8 on p53, a non-histone substrate, suggests the important function of KAT8 Tudor-knot domain in the substrate specific catalytic regulation.
2023-12-24 | GSE245007 | GEO
Project description:Tudor-knot domain mutation in KAT8/MOF impede nucleosome interaction and histone acetylation
| PRJNA1026608 | ENA
Project description:Tudor-knot domain mutation in KAT8/MOF impede nucleosome interaction and histone acetylation [RNA-Seq]
| PRJNA1026612 | ENA
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:This SuperSeries is composed of the SubSeries listed below.
2023-12-24 | GSE245009 | GEO
Project description:Dysregulation of MOF (MYST1, KAT8), a highly conserved H4K16 acetyltransferase, plays important roles in human cancers. However, its expression and function in esophageal squamous cell carcinoma (ESCC) remain unknown. Here, we report that MOF is highly expressed in ESCC tumors and predicts a worse prognosis. Depletion of MOF in ESCC significantly impedes tumor growth and metastasis both in vitro and in vivo, whereas ectopic expression of MOF but not enzyme inactive mutant (MOF E350Q) promotes ESCC progression, suggesting that MOF acetyltransferase activity is crucial for its oncogenic activity. Further analysis reveals that USP10, a deubiquitinase highly expressed in ESCC, binds to and protects MOF from proteosome-dependent protein degradation. MOF stabilization by USP10 promotes H4K16ac enrichment in the ANXA2 promoter to stimulate ANXA2 transcription, which subsequently activates Wnt/ β-Catenin signaling to facilitate ESCC progression. Our findings highlight a novel USP10/MOF/ANXA2 axis as a promising therapeutic target for ESCC.
2024-01-09 | GSE241066 | GEO
Project description:Histone acetylation is associated with open chromatin and transcriptionally active genes. Specifically, acetylation of lysine 16 on histone H4 (H4K16ac) has been shown to prevent the assembly of nucleosomal arrays in vitro. This modification is catalyzed by the MYST-family histone acetyltransferase KAT8 (also known as MOF and MYST1), which is part of two distinct chromatin-associated complexes: NSL and MSL. While extensively studied in Drosophila, the functions of H4K16ac and the two KAT8-containing complexes in mammalian cells are not well understood. Here, we demonstrate a surprising complex-dependent activity of KAT8. We found that KAT8 catalyzes H4K5 and H4K8 acetylation as part of the NSL complex, whereas it catalyzes the bulk of H4K16 acetylation as part of the MSL complex. Furthermore, we show that the core proteins of the MSL complex and H4K16ac are not required for cell proliferation and global chromatin accessibility, whereas the NSL complex is essential for cell survival, as it is enriched at the promoters of housekeeping genes and is required for their transcription initiation. In summary, we show that KAT8 switches catalytic activity and function depending on its associated proteins, and that, as part of the NSL complex, it catalyzes H4K5 and H4K8 acetylation required for the expression of genes essential for cell survival.
2021-02-28 | GSE158521 | GEO
Project description:Role of the Tudor-knot domain of the TIP60 lysine acetyltransferase [RNA-seq]
| PRJNA1026964 | ENA