K562 cells implicate increased chromatin accessibility in Alu transcriptional activation

Li, Tzu-Huey; Kim, Cheonkoog; Rubin, Carol M.; Schmid, Carl W.

doi:10.1093/nar/28.16.3031

Cited by 39 publications

(34 citation statements)

References 56 publications

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“…Activation of repeats resulting from combined lack of TP53 function and DNA methylation was followed by induction of the type I IFN signaling pathway (29). Loss of TP53 function and hypomethylation occur naturally in tumors, and transcription of normally silent and heavily methylated sequences that represent repeats has been shown to occur in tumors (30,31). In present study, we showed that ALU (SINEs) and LINE1 had significantly lower methylation levels in TP53-mutated tumors compared with wild-type.…”

Section: Discussionmentioning

confidence: 47%

DNA Methylation Status of Key Cell-Cycle Regulators Such as CDKNA2/p16 and CCNA1 Correlates with Treatment Response to Doxorubicin and 5-Fluorouracil in Locally Advanced Breast Tumors

Klajic

Busato

Edvardsen

et al. 2014

Clinical Cancer Research

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Purpose: To explore alterations in gene promoter methylation as a potential cause of acquired drug resistance to doxorubicin or combined treatment with 5-fluorouracil and mitomycin C in human breast cancers.Experimental Design: Paired tumor samples from locally advanced breast cancer patients treated with doxorubicin and 5-fluorouracil-mitomycin C were used in the genome-wide DNA methylation analysis as discovery cohort. An enlarged cohort from the same two prospective studies as those in the discovery cohort was used as a validation set in pyrosequencing analysis.Results: A total of 469 genes were differentially methylated after treatment with doxorubicin and revealed a significant association with canonical pathways enriched for immune cell response and cell-cycle regulating genes including CDKN2A, CCND2, CCNA1, which were also associated to treatment response. Treatment with FUMI resulted in 343 differentially methylated genes representing canonical pathways such as retinoate biosynthesis, gai signaling, and LXR/RXR activation. Despite the clearly different genes and pathways involved in the metabolism and therapeutic effect of both drugs, 46 genes were differentially methylated before and after treatment with both doxorubicin and FUMI. DNA methylation profiles in genes such as BRCA1, FOXC1, and IGFBP3, and most notably repetitive elements like ALU and LINE1, were associated with TP53 mutations status.Conclusion: We identified and validated key cell-cycle regulators differentially methylated before and after neoadjuvant chemotherapy such as CDKN2A and CCNA1 and reported that methylation patterns of these genes may be potential predictive markers to anthracycline/mitomycine sensitivity. Clin Cancer Res; 20(24); 6357-66. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 47%

DNA Methylation Status of Key Cell-Cycle Regulators Such as CDKNA2/p16 and CCNA1 Correlates with Treatment Response to Doxorubicin and 5-Fluorouracil in Locally Advanced Breast Tumors

Klajic

Busato

Edvardsen

et al. 2014

Clinical Cancer Research

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“…For example, aberrant overexpression of satellite repeats was reported recently in pancreatic and other epithelial human cancers (18). In addition, hypomethylation and activation of polymerase III-driven Alu (the only major SINE in the human genome) transcription was found in human tumors (44,45). TRAIN is likely to be the explanation for the previously described phenomenon of inhibition of growth of pancreatic tumor cells by 5-aza-dC accompanied with the induction of IFN response signaling (46).…”

Section: Discussionmentioning

confidence: 84%

p53 cooperates with DNA methylation and a suicidal interferon response to maintain epigenetic silencing of repeats and noncoding RNAs

Leonova

Brodsky

Lipchick

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

235

254

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Large parts of mammalian genomes are transcriptionally inactive and enriched with various classes of interspersed and tandem repeats. Here we show that the tumor suppressor protein p53 cooperates with DNA methylation to maintain silencing of a large portion of the mouse genome. Massive transcription of major classes of short, interspersed nuclear elements (SINEs) B1 and B2, both strands of near-centromeric satellite DNAs consisting of tandem repeats, and multiple species of noncoding RNAs was observed in p53-deficient but not in p53 wild-type mouse fibroblasts treated with the DNA demethylating agent 5-aza-2'-deoxycytidine. The abundance of these transcripts exceeded the level of β-actin mRNA by more than 150-fold. Accumulation of these transcripts, which are capable of forming double-stranded RNA (dsRNA), was accompanied by a strong, endogenous, apoptosis-inducing type I IFN response. This phenomenon, which we named "TRAIN" (for "transcription of repeats activates interferon"), was observed in spontaneous tumors in two models of cancer-prone mice, presumably reflecting naturally occurring DNA hypomethylation and p53 inactivation in cancer. These observations suggest that p53 and IFN cooperate to prevent accumulation of cells with activated repeats and provide a plausible explanation for the deregulation of IFN function frequently seen in tumors. Overall, this work reveals roles for p53 and IFN that are key for genetic stability and therefore relevant to both tumorigenesis and the evolution of species.interferon alpha-beta receptor | RNA sequencing | epigenetic repression | microarray hybridization

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“…It is known that chromatin undergoes decondensation under cell stresses caused by different factors, e.g., heat shock, viral infection or inhibition of protein synthesis (Li et al 2000;Kim et al 2001). From the standpoint of cell membrane-dependent chromatin condensation, this can be explained by partial membrane permeabilization and/or diminishing ability of the active transport systems to maintain the necessary gradients in extra/intracellular solute compositions.…”

Section: Effect Of Elevated Salinitymentioning

confidence: 99%

Genome size and chromatin condensation in vertebrates

Vinogradov

2005

Chromosoma

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Cell membrane-dependent chromatin condensation was studied by flow cytometry in erythrocytes of 36 species from six classes of vertebrates. A positive relationship was found between the degree of condensation and genome size. The distribution of variances among taxonomic levels is similar for both parameters. However, chromatin condensation varied relatively more at the lower taxonomic levels, which suggests that the degree of DNA packaging might serve for fine-tuning the 'skeletal' and/or 'buffering' function of noncoding DNA (although the range of this fine-tuning is smaller than the range of genome size changes). For two closely related amphibian species differing in genome size, change in chromatin condensation under the action of elevated extracellular salinity was investigated. Condensation was steadier and its reaction to changes in solvent composition was more inertial in the species with a larger genome, which is in agreement with the buffering function postulated for redundant DNA. The uppermost genome size in vertebrates (and in living beings in general) was updated using flow cytometry and was found to be about 80 pg (78,400 Mb). The widespread opinion that the largest genome occurs in unicellular organisms is rejected as being based on artifacts.

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K562 cells implicate increased chromatin accessibility in Alu transcriptional activation

Cited by 39 publications

References 56 publications

DNA Methylation Status of Key Cell-Cycle Regulators Such as CDKNA2/p16 and CCNA1 Correlates with Treatment Response to Doxorubicin and 5-Fluorouracil in Locally Advanced Breast Tumors

DNA Methylation Status of Key Cell-Cycle Regulators Such as CDKNA2/p16 and CCNA1 Correlates with Treatment Response to Doxorubicin and 5-Fluorouracil in Locally Advanced Breast Tumors

p53 cooperates with DNA methylation and a suicidal interferon response to maintain epigenetic silencing of repeats and noncoding RNAs

Genome size and chromatin condensation in vertebrates

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