Coordinate H3K9 and DNA methylation silencing of ZNFs in toxicant-induced malignant transformation

Severson, Paul; Tokar, Erik J.; Vrba, Lukáš; Waalkes, Michael P.; Futscher, Bernard W.

doi:10.4161/epi.25926

Cited by 35 publications

(28 citation statements)

References 51 publications

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“…Interestingly, Chen and colleagues (Chen et al., 2016) have recently demonstrated that normal tissue signatures are better predictors of DNA hypermethylation changes than ESC signatures. Furthermore, hypermethylation changes were also associated with the repressive histone mark H3K9me3 (Ohm et al., 2007), which was correlated to ZNF genes and DNA repeats in our chromatin state analyses, and which might have a potential relationship with the malignant transformation process (Severson, Tokar, Vrba, Waalkes & Futscher, 2013). …”

Section: Discussionmentioning

confidence: 76%

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

et al. 2018

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SummaryCancer is an aging‐associated disease, but the underlying molecular links between these processes are still largely unknown. Gene promoters that become hypermethylated in aging and cancer share a common chromatin signature in ES cells. In addition, there is also global DNA hypomethylation in both processes. However, the similarity of the regions where this loss of DNA methylation occurs is currently not well characterized, and it is unknown if such regions also share a common chromatin signature in aging and cancer. To address this issue, we analyzed TCGA DNA methylation data from a total of 2,311 samples, including control and cancer cases from patients with breast, kidney, thyroid, skin, brain, and lung tumors and healthy blood, and integrated the results with histone, chromatin state, and transcription factor binding site data from the NIH Roadmap Epigenomics and ENCODE projects. We identified 98,857 CpG sites differentially methylated in aging and 286,746 in cancer. Hyper‐ and hypomethylated changes in both processes each had a similar genomic distribution across tissues and displayed tissue‐independent alterations. The identified hypermethylated regions in aging and cancer shared a similar bivalent chromatin signature. In contrast, hypomethylated DNA sequences occurred in very different chromatin contexts. DNA hypomethylated sequences were enriched at genomic regions marked with the activating histone posttranslational modification H3K4me1 in aging, while in cancer, loss of DNA methylation was primarily associated with the repressive H3K9me3 mark. Our results suggest that the role of DNA methylation as a molecular link between aging and cancer is more complex than previously thought.

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Section: Discussionmentioning

confidence: 76%

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

et al. 2018

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“…Interestingly, Chen and colleagues [36] have recently demonstrated that normal-tissue signatures are better predictors of DNA hypermethylation changes than ESC signatures. Furthermore, hypermethylation changes were also associated with the repressive histone mark H3K9me3 [6,43], which was correlated to ZNF genes and DNA repeats in our chromatin state analyses, and which might have a potential relationship with the malignant transformation process [43,44].…”

Section: Discussionmentioning

confidence: 99%

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

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Tejedor

Bayón

et al. 2017

Preprint

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BackgroundCancer is an aging-associated disease but the underlying molecular links between these processes are still largely unknown. Gene promoters that become hypermethylated in aging and cancer share a common chromatin signature in ES cells. In addition, there is also global DNA hypomethylation in both processes. However, any similarities of the regions where this loss of DNA methylation occurs is currently not well characterized, nor is it known whether such regions also share a common chromatin signature in aging and cancer.ResultsTo address this issue we analysed TCGA DNA methylation data from a total of 2,311 samples, including control and cancer cases from patients with breast, kidney, thyroid, skin, brain and lung tumors and healthy blood, and integrated the results with histone, chromatin state and transcription factor binding site data from the NIH Roadmap Epigenomics and ENCODE projects. We identified 98,857 CpG sites differentially methylated in aging, and 286,746 in cancer. Hyper- and hypomethylated changes in both processes each had a similar genomic distribution across tissues and displayed tissue-independent alterations. The identified hypermethylated regions in aging and cancer shared a similar bivalent chromatin signature. In contrast, hypomethylated DNA sequences occurred in very different chromatin contexts. DNA hypomethylated sequences were enriched at genomic regions marked with the activating histone posttranslational modification H3K4me1 in aging, whilst in cancer, loss of DNA methylation was primarily associated with the repressive H3K9me3 mark.ConclusionsOur results suggest that the role of DNA methylation as a molecular link between aging and cancer is more complex than previously thought.

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“…Strikingly, four of the 20 genes encoded zinc finger proteins (ZNFs). Individual ZNFs and even some clusters of ZNF genes have been found hypermethylated and silenced in several tumour types [43][44][45][46] . In addition, methylation of other ZNF genes have potential prognostic value in prostate and bladder cancer 47,48 .…”

Section: Articlementioning

confidence: 99%

Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value

et al. 2015

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Epigenetic alterations in the cancer methylome are common in breast cancer and provide novel options for tumour stratification. Here, we perform whole-genome methylation capture sequencing on small amounts of DNA isolated from formalin-fixed, paraffin-embedded tissue from triple-negative breast cancer (TNBC) and matched normal samples. We identify differentially methylated regions (DMRs) enriched with promoters associated with transcription factor binding sites and DNA hypersensitive sites. Importantly, we stratify TNBCs into three distinct methylation clusters associated with better or worse prognosis and identify 17 DMRs that show a strong association with overall survival, including DMRs located in the Wilms tumour 1 (WT1) gene, bi-directional-promoter and antisense WT1-AS. Our data reveal that coordinated hypermethylation can occur in oestrogen receptor-negative disease, and that characterizing the epigenetic framework provides a potential signature to stratify TNBCs. Together, our findings demonstrate the feasibility of profiling the cancer methylome with limited archival tissue to identify regulatory regions associated with cancer.

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Coordinate H3K9 and DNA methylation silencing of ZNFs in toxicant-induced malignant transformation

Cited by 35 publications

References 51 publications

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value

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