Dataset Information

Redox-active quinones induces genome-wide DNA methylation changes by an iron-mediated and Tet-dependent mechanism.

ABSTRACT: DNA methylation has been proven to be a critical epigenetic mark important for various cellular processes. Here, we report that redox-active quinones, a ubiquitous class of chemicals found in natural products, cancer therapeutics and environment, stimulate the conversion of 5 mC to 5 hmC in vivo, and increase 5 hmC in 5751 genes in cells. 5 hmC increase is associated with significantly altered gene expression of 3414 genes. Interestingly, in quinone-treated cells, labile iron-sensitive protein ferritin light chain showed a significant increase at both mRNA and protein levels indicating a role of iron regulation in stimulating Tet-mediated 5 mC oxidation. Consistently, the deprivation of cellular labile iron using specific chelator blocked the 5 hmC increase, and a delivery of labile iron increased the 5 hmC level. Moreover, both Tet1/Tet2 knockout and dimethyloxalylglycine-induced Tet inhibition diminished the 5 hmC increase. These results suggest an iron-regulated Tet-dependent DNA demethylation mechanism mediated by redox-active biomolecules.

SUBMITTER: Zhao B

PROVIDER: S-EPMC3919571 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Redox-active quinones induces genome-wide DNA methylation changes by an iron-mediated and Tet-dependent mechanism.

Zhao Bailin B Yang Ying Y Wang Xiaoli X Chong Zechen Z Yin Ruichuan R Song Shu-Hui SH Zhao Chao C Li Cuiping C Huang Hua H Sun Bao-Fa BF Wu Danni D Jin Kang-Xuan KX Song Maoyong M Zhu Ben-Zhan BZ Jiang Guibin G Rendtlew Danielsen Jannie M JM Xu Guo-Liang GL Yang Yun-Gui YG Wang Hailin H

Nucleic acids research 20131108 3

DNA methylation has been proven to be a critical epigenetic mark important for various cellular processes. Here, we report that redox-active quinones, a ubiquitous class of chemicals found in natural products, cancer therapeutics and environment, stimulate the conversion of 5 mC to 5 hmC in vivo, and increase 5 hmC in 5751 genes in cells. 5 hmC increase is associated with significantly altered gene expression of 3414 genes. Interestingly, in quinone-treated cells, labile iron-sensitive protein f ...[more]

PMID: 24214992

Similar Datasets

Project description:Abstract Pharmacological ascorbate (P-AscH-; high dose intravenous infusions of vitamin C generating milli-molar plasma concentrations) has re-emerged as an anti-cancer therapy. Phase 1 clinical trials combining P-AscH- with chemotherapy and ionizing radiation demonstrate safety and promising clinical outcomes in a variety of malignancies. In a first-in-human trial, subjects with newly diagnosed glioblastoma (GBM) and undetectable MGMT promoter methylation were treated with P-AscH-, ionizing radiation, and temozolomide. Results demonstrate median progression-free survival (PFS) of 10 months and median overall survival (OS) of 23 months, comparing favorably to historical GBM patients expressing MGMT. P-AscH-‘s anti-cancer mechanism is dependent upon the presence of redox active labile iron. In the presence of redox active iron, the formation of hydrogen peroxide, which causes oxidative stress and eventual cell death, selectively forms in cancer cells. Treatment with P-AscH- increased cancer cells’ labile iron pool, further enhancing sensitivity to P-AscH-. We investigated the capability of MR imaging (T2* relaxation time) to measure the redox active iron and predict response to P-AscH-. T2* relaxation time is influenced by in-field inhomogeneities, such as redox active paramagnetic iron. The active phase 2 trial evaluating P-AscH-, radiation, and temozolomide for GBM, obtains T2* imaging prior to (baseline) and immediately after ascorbate infusion (NCT02344355). A preliminary analysis of the baseline scan for the first 15 subjects suggests those with faster GBM T2* relaxation times (≤ 58 ms) have more redox active labile iron pools as well as an improved median PFS (11.4 months) compared to those with slower T2* relaxation times (> 58 ms; median PFS of 8.5 months). Pre-clinical studies evaluating the effectiveness of iron nano-particle supplementation in GBM animal models are on-going. (Supported by P01 CA217797, R01 CA169046, U01 CA140206, T32 CA078586, P30 CA086862, as well as the Gateway for Cancer Research grant G-17–1500.)

Project description:Conjugated arrays composed of corrole macrocycles are increasingly more common, but their chemistry still lags behind that of their porphyrin counterparts. Here, we report on the insertion of iron(III) into a β,β-fused corrole dimer and on the electronic effects that this redox active metal center has on the already rich coordination chemistry of [H3tpfc] COT, where COT = cyclo-octatetraene and tpfc = tris(pentafluorophenyl)corrole. Synthetic manipulations were performed for the isolation and full characterization of both the 5-coordinate [FeIIItpfc(py)]2COT and 6-coordinate [FeIIItpfc(py)2]2COT, with one and two axial pyridine ligands per metal, respectively. X-Ray crystallography reveals a dome-shaped structure for [FeIIItpfc(py)]2COT and a perfectly planar geometry which (surprisingly at first) is also characterized by shorter Fe-N (corrole) and Fe-N (pyridine) distances. Computational investigations clarify that the structural phenomena are due to a change in the iron(III) spin state from intermediate (S = 3/2) to low (S = 1/2), and that both the 5- and 6-coordinated complexes are enthalpically favored. Yet, in contrast to iron(III) porphyrins, the formation enthalpy for the coordination of the first pyridine to Fe(III) corrole is more negative than that of the second pyridine coordination. Possible interactions between the two corrole subunits and the chelated iron ions were examined by UV-Vis spectroscopy, electrochemical techniques, and density functional theory (DFT). The large differences in the electronic spectra of the dimer relative to the monomer are concluded to be due to a reduced electronic gap, owing to the extensive electron delocalization through the fusing bridge. A cathodic sweep for the dimer discloses two redox processes, separated by 230 mV. The DFT self-consistent charge density for the neutral and cationic states (1- and 2-electron oxidized) reveals that the holes are localized on the macrocycle. A different picture emerges from the reduction process, where both the electrochemistry and the calculated charge density point toward two consecutive electron transfers with similar energetics, indicative of very weak electron communication between the two redox active iron(III) sites. The binuclear complex was determined to be a much better catalyst for the electrochemical hydrogen evolution reaction (HER) than the analogous mononuclear corrole.

Dataset Information

Redox-active quinones induces genome-wide DNA methylation changes by an iron-mediated and Tet-dependent mechanism.

Publications

Redox-active quinones induces genome-wide DNA methylation changes by an iron-mediated and Tet-dependent mechanism.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets