Inhibition of SF3A2 acetylation at lysine 10 mediated by p300/SIRT7 promotes Fscn1 alternative splicing against myocardial ischemic/reperfusion injury
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE236473 | GEO | 2024/12/13
REPOSITORIES: GEO
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Project description:The 4D-lable free proteomic and acetylomic study were employed to gain the targets of GS. The co-immunoprecipitation, co-localization, and specific acetylation site antibody were used to verify the acetylation. Based on the mass spectrometry analysis, the active monomers in GS were screened by phenotypes of acetylation and mitochondrial function. The mechanism was studied through RNA-seq, qPCR, cellular thermal shift assay, surface plasmon resonance, acetyltransferase activity combined with pharmacological inhibitor, RNA interference and site-specific mutation. These findings provide a novel mechanism underlying cardiomyocyte protection of ginsenoside Rb2 through p300/SIRT7-SF3A2-Fscn1 signaling and opens new opportunities for pharmacological prevention and treatment of ischemic and associated sequelae.
2024-12-13 | GSE236471 | GEO
Project description:Inhibition of SF3A2 acetylation at lysine 10 mediated by p300/SIRT7 promotes Fscn1 alternative splicing against myocardial ischemic/reperfusion injury
| PRJNA991442 | ENA
Project description:Inhibition of SF3A2 acetylation at lysine 10 mediated by p300/SIRT7 promotes Fscn1 alternative splicing against myocardial ischemic/reperfusion injury [RNA-Seq I]
| PRJNA991446 | ENA
Project description:ING5 belongs to the Inhibitor of Growth (ING) candidate tumor suppressor family. Previously, we have shown that ING5 inhibits invasiveness of lung cancer cells by downregulating EMT-inducing genes. However, the underlying mechanisms remain unclear. The aim of the study was to use integrated approach involving SILAC labeling and mass spectrometry-based quantitative proteomics to quantify dynamic changes of acetylation regulated by ING5 in lung cancer cells. Here, we have found that ING5 has a profound influence on protein lysine acetylation with 163 acetylation peptides on 122 proteins significantly upregulated and 100 acetylation peptides on 72 proteins downregulated by ING5 overexpression. Bioinfomatic analysis revealed that the acetylated proteins upregulated by ING5 located preferentially in nucleus to cytoplasm and were significantly enriched in transcription cofactor activity, chromatin binding and DNA binding functions; while those downregulated by ING5 located preferentially in cytoplasm rather than nucleus and were functionally enriched in metabolism, suggesting diverse functions of ING5 through differentially regulating protein acetylation. Interestingly, we found ING5 overexpression promotes p300 autoacetylation at K1555, K1558 and K1560 within p300 HAT domain, and two novel sites K1647 and K1794, leading to activation of p300 HAT activity, which was confirmed by accelerated acetylation of p300 target proteins, p53 at k382 and histone H3 at K18. A specific p300 HAT inhibitor C646 impaired ING5-increased acetylation of H3K18 and p53K382, and subsequent expression of p21 and Bax. In conclusion, our results reveal the lysine acetylome regulated by ING5 and provide new insights into mechanisms of ING5 in the regulation of gene expression, metabolism and other cellular functions.
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Project description:Acetylation within the globular core domain of histone H3 on lysine 56 (H3K56) has recently been shown to have a critical role in packaging DNA into chromatin following DNA replication and repair in budding yeast. However, the function or occurrence of this specific histone mark has not been studied in multicellular eukaryotes, mainly because the Rtt109 enzyme that is known to mediate acetylation of H3K56 (H3K56ac) is fungal-specific. Here we demonstrate that the histone acetyl transferase CBP (also known as Nejire) in flies and CBP and p300 (Ep300) in humans acetylate H3K56, whereas Drosophila Sir2 and human SIRT1 and SIRT2 deacetylate H3K56ac. The histone chaperones ASF1A in humans and Asf1 in Drosophila are required for acetylation of H3K56 in vivo, whereas the histone chaperone CAF-1 (chromatin assembly factor 1) in humans and Caf1 in Drosophila are required for the incorporation of histones bearing this mark into chromatin. We show that, in response to DNA damage, histones bearing acetylated K56 are assembled into chromatin in Drosophila and human cells, forming foci that colocalize with sites of DNA repair. Furthermore, acetylation of H3K56 is increased in multiple types of cancer, correlating with increased levels of ASF1A in these tumours. Our identification of multiple proteins regulating the levels of H3K56 acetylation in metazoans will allow future studies of this critical and unique histone modification that couples chromatin assembly to DNA synthesis, cell proliferation and cancer.
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Project description:Splicing of precursor mRNA (pre-mRNA) is an important regulatory step in gene expression. Recent evidence points to a regulatory role of chromatin-related proteins in alternative splicing regulation. Using an unbiased approach, we have identified the acetyltransferase p300 as a key chromatin-related regulator of alternative splicing. p300 promotes genome-wide exon inclusion in both a transcription-dependent and -independent manner. Using CD44 as a paradigm, we found that p300 regulates alternative splicing by modulating the binding of splicing factors to pre-mRNA. Using a tethering strategy, we found that binding of p300 to the CD44 promoter region promotes CD44v exon inclusion independently of RNAPII transcriptional elongation rate. Promoter-bound p300 regulates alternative splicing by acetylating splicing factors, leading to exclusion of hnRNP M from CD44 pre-mRNA and activation of Sam68. p300-mediated CD44 alternative splicing reduces cell motility and promotes epithelial features. Our findings reveal a chromatin-related mechanism of alternative splicing regulation and demonstrate its impact on cellular function.
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Project description:Histone acetylation modulates alternative splicing of several hundred genes. Here, we tested the role of the histone acetyltransferase p300 in alternative splicing and showed that knockdown of p300 promotes inclusion of the fibronectin (FN1) alternative EDB exon. p300 associates with CRE sites in the promoter via the CREB transcription factor. We created mini-gene reporters driven by an artificial promoter containing CRE sites. Both deletion and mutation of the CRE site affected EDB alternative splicing in the same manner as p300 knockdown. Next we showed that p300 controls histone H4 acetylation along the FN1 gene. Consistently, p300 depletion and CRE deletion/mutation both reduced histone H4 acetylation on mini-gene reporters. Finally, we provide evidence that the effect of CRE inactivation on H4 acetylation and alternative splicing is counteracted by the inhibition of histone deacetylases. Together, these data suggest that histone acetylation could be one of the mechanisms how promoter and promoter binding proteins influence alternative splicing.
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Project description:Histone posttranslational modifications and chromatin dynamics are inextricably linked to eukaryotic gene expression. Among the many modifications that have been characterized, histone tail acetylation is most strongly correlated with transcriptional activation. In Metazoa, promoters of transcriptionally active genes are generally devoid of physically repressive nucleosomes, consistent with the contemporaneous binding of the large RNA polymerase II transcription machinery. The histone acetyltransferase p300 is also detected at active gene promoters, flanked by regions of histone hyperacetylation. Although the correlation between histone tail acetylation and gene activation is firmly established, the mechanisms by which acetylation facilitates this fundamental biological process remain poorly understood. To explore the role of acetylation in nucleosome dynamics, we utilized an immobilized template carrying a natural promoter reconstituted with various combinations of wild-type and mutant histones. We find that the histone H3 N-terminal tail is indispensable for activator, p300, and acetyl-CoA-dependent nucleosome eviction mediated by the histone chaperone Nap1. Significantly, we identify H3 lysine 14 as the essential p300 acetylation substrate required for dissociation of the histone octamer from the promoter DNA. Together, a total of 11 unique mutant octamer sets corroborated these observations and revealed a striking correlation between nucleosome eviction and strong activator and acetyl-CoA-dependent transcriptional activation. These novel findings uncover an exclusive role for H3 lysine 14 acetylation in facilitating the ATP-independent and transcription-independent disassembly of promoter nucleosomes by Nap1. Furthermore, these studies directly couple nucleosome disassembly with strong, activator-dependent transcription.
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Project description:Nuclear factor kappaB (NF-kappaB) plays an important role in the transcriptional regulation of genes involved in immunity and cell survival. We show here in vitro and in vivo acetylation of RelA/p65 by p300 on lysine 314 and 315, two novel acetylation sites. Additionally, we confirmed the acetylation on lysine 310 shown previously. Genetic complementation of RelA/p65-/- cells with wild type and non-acetylatable mutants of RelA/p65 (K314R and K315R) revealed that neither shuttling, DNA binding nor the induction of anti-apoptotic genes by tumor necrosis factor alpha was affected by acetylation on these residues. Microarray analysis of these cells treated with TNFalpha identified specific sets of genes differently regulated by wild type or acetylation-deficient mutants of RelA/p65. Specific genes were either stimulated or repressed by the acetylation-deficient mutants when compared to RelA/p65 wild type. These results support the hypothesis that site-specific p300-mediated acetylation of RelA/p65 regulates the specificity of NF-kappaB dependent gene expression.
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