Sanguinarine, putative anticancer therapeutic, interacts, modulates and transcripts in the context of chromatin
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE14777 | GEO | 2011/09/12
SECONDARY ACCESSION(S): PRJNA112205
REPOSITORIES: GEO
Similar Datasets
Project description:DNA binding anticancer agents cause alteration in chromatin structure and dynamics. Here, we report the dynamic interaction of the DNA intercalator and potential anticancer, plant alkaloid, Sanguinarine (SGR) with chromatin. Association of SGR with different levels of chromatin structure was found to be enthalpydriven. Apart from DNA it binds with comparable affinity to histones and induces chromatin aggregation. The dual binding property of SGR leads to inhibition of core histone modifications. Although, it potently inhibits H3K9 methylation by G9a in vitro, H3K4 and H3R17 methylation are more profoundly inhibited in cells. SGR inhibits histone acetylation both in vitro and in vivo. It does not affect the in vitro transcription from DNA template but significantly represses acetylation dependent chromatin transcription. SGR mediated repression of epigenetic marks and the alteration of chromatin geography, also result in modulation of global gene expression. These data conclusively, show the anticancer DNA binding intercalator as a modulator of chromatin modifications and transcription in the chromatin context.
2009-02-28 | GSE14314 | GEO
Project description:DNA binding anticancer agents cause alteration in chromatin structure and dynamics. Here, we report the dynamic interaction of the DNA intercalator and potential anticancer, plant alkaloid, Sanguinarine (SGR) with chromatin. Association of SGR with different levels of chromatin structure was found to be enthalpydriven. Apart from DNA it binds with comparable affinity to histones and induces chromatin aggregation. The dual binding property of SGR leads to inhibition of core histone modifications. Although, it potently inhibits H3K9 methylation by G9a in vitro, H3K4 and H3R17 methylation are more profoundly inhibited in cells. SGR inhibits histone acetylation both in vitro and in vivo. It does not affect the in vitro transcription from DNA template but significantly represses acetylation dependent chromatin transcription. SGR mediated repression of epigenetic marks and the alteration of chromatin geography, also result in modulation of global gene expression. These data conclusively, show the anticancer DNA binding intercalator as a modulator of chromatin modifications and transcription in the chromatin context. The total RNA was isolated from control and treated cells using TRIZOL (Invitrogen) method. The Micromax direct labeling kit, MPS502 (PerkinElmer) was used to synthesize the labeled cDNA from 70 ug of total RNA and further process the hybridized cDNA on the array. All the steps were carried out according to manufacturerâs instructions (www.perkinelmer.com/lifesciences). The array slides were scanned immediately by PerkinElmer Scan array Gx Microarray scanner. The Scan array software (PerkinElmer) was used for grid wise normalization of array images. Two arrays were used with at least one biological treatment of cells and dye swap experiment were included in the final analysis. . The data was analysed by GeneSpring GX and Biointerpreter software from Genotypic Technology, Bangalore. The differential expression was considered if the Log 2 mean of at least -1 for the down regulated genes and +1 for the upregulated genes. We considered only the genes that were reproducible from both replicates.
2010-05-22 | E-GEOD-14314 | biostudies-arrayexpress
Project description:DNA-binding anticancer agents cause alteration in chromatin structure and dynamics. Here, we report the dynamic interaction of the DNA intercalator and potential anticancer, plant alkaloid, sanguinarine (SGR) with chromatin. Association of SGR with different levels of chromatin structure was found to be enthalpy driven. Apart from DNA, it binds with comparable affinity to histones and induces chromatin aggregation. The dual binding property of SGR leads to inhibition of core histone modifications. Although it potently inhibits H3K9 methylation by G9a in vitro, H3K4 and H3R17 methylation are more profoundly inhibited in cells. SGR inhibits histone acetylation both in vitro and in vivo. It does not affect the in vitro transcription from DNA template but significantly represses acetylation-dependent chromatin transcription. SGR mediated repression of epigenetic marks and the alteration of chromatin geography also result in modulation of global gene expression. These data conclusively show that the anticancer DNA-binding intercalator as a modulator of chromatin modifications and transcription in the chromatin context. The total RNA was isolated from control and treated cells using the TRIzol (Invitrogen) method. The Micromax direct labeling kit, MPS502 (PerkinElmer), was used to synthesize the labeled cDNA from 70 ug of total RNA and further process the hybridized cDNA on the array. All the steps were carried out according to manufacturer’s instructions (www.perkinelmer.com/lifesciences). The array slides were scanned immediately by the PerkinElmer Scan array Gx Microarray scanner. The Scan array software (PerkinElmer) was used for grid wise normalization of array images. Five arrays were used with at least two biological treatments of cells, and dye-swap experiments were included in the final analysis. The data was analysed by GeneSpring GX and Biointerpreter software from Genotypic Technology, Bangalore. The differential expression was considered if the Log 2 mean of at least -1 for the downregulated genes and +1 for the upregulated genes. We considered only the genes that were reproducible from all five replicates.
2011-09-11 | E-GEOD-14777 | biostudies-arrayexpress
Project description:Polycomb Group (PcG) proteins regulate gene expression by modifying chromatin. A key PcG complex, PRC1, has two activities: a ubiquitin ligase activity for histone H2A, and a chromatin compacting/nucleosome bridging activity that can inhibit transcription and chromatin remodeling. In Drosophila, the Posterior Sex Combs (PSC) subunit of PRC1 is central to both activities. The N-terminal homology region (HR) of PSC partners with dRING to form the ubiquitin ligase, while its intrinsically disordered C-terminal region (PSC-CTR) compacts chromatin, and inhibits chromatin remodeling and transcription in vitro. Both the HR and the PSC-CTR are essential in vivo. To understand how these two activities may be coordinated in PRC1, we used cross-linking mass spectrometry (XL-MS) to analyze the conformations of the PSC-CTR in PRC1 and how they change on binding DNA. XL-MS identifies interactions between the PSC-CTR and the core of PRC1, including the PSC HR. New contacts and overall more compacted PSC-CTR conformations are induced by DNA binding. We used chemical acetylation of accessible lysines for MS-based protein footprinting of the PSC-CTR. Protein footprinting reveals an extended, bipartite candidate DNA/chromatin binding surface. Our data suggest a model in which DNA (or chromatin) follows a long path on the flexible PSC-CTR. Intramolecular interactions of the PSC-CTR detected by XL-MS can bring the high affinity DNA/chromatin binding region close to the core of PRC1 without disrupting the interface between the ubiquitin ligase and the nucleosome. Our approach may be applicable to understanding the global organization of other large IDRs that bind nucleic acids.
2020-05-15 | MSV000085418 | MassIVE
Project description:Jaiswal2017 - Cell cycle arrest
This model is described in the article:
ATM/Wip1 activities at
chromatin control Plk1 re-activation to determine G2 checkpoint
duration.
Jaiswal H, Benada J, Müllers E,
Akopyan K, Burdova K, Koolmeister T, Helleday T, Medema RH,
Macurek L, Lindqvist A.
EMBO J. 2017 Jul; 36(14):
2161-2176
Abstract:
After DNA damage, the cell cycle is arrested to avoid
propagation of mutations. Arrest in G2 phase is initiated by
ATM-/ATR-dependent signaling that inhibits mitosis-promoting
kinases such as Plk1. At the same time, Plk1 can counteract
ATR-dependent signaling and is required for eventual resumption
of the cell cycle. However, what determines when Plk1 activity
can resume remains unclear. Here, we use FRET-based reporters
to show that a global spread of ATM activity on chromatin and
phosphorylation of ATM targets including KAP1 control Plk1
re-activation. These phosphorylations are rapidly counteracted
by the chromatin-bound phosphatase Wip1, allowing cell cycle
restart despite persistent ATM activity present at DNA lesions.
Combining experimental data and mathematical modeling, we
propose a model for how the minimal duration of cell cycle
arrest is controlled. Our model shows how cell cycle restart
can occur before completion of DNA repair and suggests a
mechanism for checkpoint adaptation in human cells.
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BIOMD0000000641.
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2014-03-28 | BIOMD0000000641 | BioModels
Project description:Chromatin relaxation is a prerequisite step that allows the DNA repair machinery to access double-strand breaks (DSBs), and local histones around the DNA breaks suffer from prompt acetylation changes. However, an intriguing question remains as to where the large demands of acetyl-CoA is precisely produced promptly. Here, we report that pyruvate dehydrogenase 1α (PDHE1α) catalyzes pyruvate metabolism to provide acetyl-CoA promptly in response to DNA damage. PDHE1α was quickly recruited to chromatin in a PARylation-dependent manner, which further drove acetyl-CoA generation to support local chromatin acetylation around the DSB regions. In turn, this process increased the formation of relaxed chromatin to benefit repair factor loading, thus promoting DSB repair to ultimately maintain genome stability and contribute to the resistance of cancer cells to DNA-damaging treatments in vitro and in vivo. In accordance with this, blocking PARylation-based PDHE1α chromatin recruitment markedly attenuated chromatin relaxation and the DSB repair efficiency, resulting in genome instability and restoration of radiosensitivity. Collectively, these findings reveal an undescribed mechanism that underlies site-directed acetyl-CoA generation involving chromatin-associated PDHE1α and its instrumental function in DNA repair and regulating local chromatin acetylation around DSB sites.
2023-07-27 | PXD040676 | Pride
Project description:The Polycomb protein Polyhomeotic (Ph) is implicated in organizing chromatin to regulate gene expression. This activity depends on the sterile alpha motif in Ph, which can form helical polymers. This polymerization activity is believed to create macromolecular assemblies of Polycomb proteins and chromatin in cells. To understand how this may occur, and the possible role of phase separation in the process, we analyzed a truncated version of Ph (aa1289-1577, Mini-Ph) in vitro. We find that Mini-Ph forms phase separated condensates with DNA or chromatin in vitro. To understand how Ph SAM polymerization contributes to this activity, and how Mini-Ph conformation might change on binding DNA and phase separating, we used a protein footprinting method based on chemical acetylation of accessible lysine residues. Mini-Ph or a polymerization mutant, alone, or with DNA, was treated with sulfo-NHS-acetate to acetylate accessible lysines. After protein denaturation, the protein was treated with propionic acid to propionylate unacetylated lysines. Samples were analyzed by MS, and the ratio of acetylated/propionylated lysines quantified at each position using MaxQuant.
2020-07-10 | MSV000085717 | MassIVE
Project description:Chelerythrine (CHL), a plant alkaloid, possesses antimicrobial, anti-inflammatory and antitumor properties. Although CHL influences several key signal transduction pathways, its ability to interact directly with nucleoprotein complex chromatin, in eukaryotic cells has so far not been looked into. Here we have demonstrated its association with hierarchically assembled chromatin components viz. long chromatin, chromatosome, nucleosome, chromosomal DNA and histone H3 and the consequent effect on chromatin structure. CHL was found to repress acetylation at H3K9. It is more target-specific in terms of gene expression alteration and less cytotoxic compared to its structural analogue sanguinarine.
2017-04-28 | GSE80752 | GEO
Project description:Aberrations in chromatin dynamics play a fundamental role in tumorigenesis, yet relatively little is known of the molecular mechanisms linking histone lysine methylation to neoplastic disease. ING4 (Inhibitor of Growth 4) is a native subunit of an HBO1 histone acetyltransferase (HAT) complex and a tumor suppressor protein. Here we show a critical role for the specific read-out of histone H3 trimethylated at lysine 4 (H3K4me3) by the ING4 PHD finger in mediating ING4 gene expression and tumor suppressor functions. The interaction between ING4 and H3K4me3 augments the acetylation activity of HBO1 on H3 tails, and drives H3 acetylation at ING4 target promoters to effect a DNA damage-dependent gene expression program. Further, ING4 facilitates apoptosis in response to genotoxic stress and inhibits anchorage-independent cell growth, and these functions are dependent on ING4 interactions with H3K4me3. Together, our results demonstrate a mechanism for brokering crosstalk between H3K4 methylation and histone H3 acetylation, and reveal a new molecular link between chromatin modulation and tumor suppressor mechanisms. ING4 ChIP-chip +/- Doxorubicin treatment in HT1080 cells on Nimblegen whole genome promoter array 4 samples: HT1080 cell lines stably expressing Flag-ING4 or Flag-ING4-D213A, +/- doxorubicin
2010-05-17 | E-GEOD-13412 | biostudies-arrayexpress
Project description:In this study, we showed chromatin accessibility-based epigenetic landscape in osteoclastogenesis. To reveal the affected genes by alteration in histone acetylation states after RANKL stimulation, we supplemented sodium acetate, which increased histone acetylation, to OC precursors. Then we conducted RNA-seq with BMM (D0), OC precursors (D1), and OC precursors treaed with sodium acetate (ACD1).
2023-01-01 | GSE212722 | GEO