Role of DNA Methylation and Epigenetic Silencing of HAND2 in Endometrial Cancer Development

Jones, Allison; Teschendorff, Andrew E.; Li, Quanxi; Hayward, Jane; Kannan, Athilakshmi; Mould, Tim; West, James D.; Zikán, Michal; Cibula, David; Fiegl, Heidi; Lee, Shih-Han; Wik, Elisabeth; Hadwin, Richard; Arora, Rupali; Lemech, Charlotte; Turunen, Henna; Pakarinen, Päivi; Jacobs, Ian; Salvesen, Helga B.; Bagchi, Milan K.; Bagchi, Indrani C.; Widschwendter, Martin

doi:10.1371/journal.pmed.1001551

Cited by 137 publications

(156 citation statements)

References 44 publications

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“…The results corroborated the data obtained from the methylation arrays and suggest that our genome-wide data can be extrapolated to independent sample sets of MSCs. HAND2 and SIX2 genes, which code for transcription factors, have also been found hypermethylated in several cancer types (Rauch et al 2006;Tong et al 2010;Jones et al 2013). In contrast, the genes that are hypomethylated during MSC aging-TBX15, PITX2, and HOXA11-code for transcription factors involved in several differentiation and developmental processes (Singh et al 2005;Gross et al 2012;Gage et al 2014).…”

Section: Discussionmentioning

confidence: 99%

H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells

et al. 2014

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In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone posttranslational modifications. However, the chromatin marks associated with changes in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells (MSCs) obtained from individuals aged 2 to 92 yr identified 18,735 hypermethylated and 45,407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type-independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on nongenetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type, and chromatin context involved and that, depending on the locus, the changes can be modulated by genetic and/or external factors.

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Section: Discussionmentioning

confidence: 99%

H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells

et al. 2014

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“…Numerous epigenetic studies have investigated the role of DNA methylation (13)(14)(15), but there are few reports regarding histone methylation and its significance in endometrial cancer. To the best of our knowledge, the present study analyzed the expression of H3K4me2, H3K4me3 and H3K27me3 in endometrial tissues by immunohistochemistry for the first time, assessing the potential association between endometrial cancer progression, and the expression levels of these three markers.…”

Section: Discussionmentioning

confidence: 99%

The expression and significance of histone lysine methylation in endometrial cancer

Nan

Tao

et al. 2017

Oncol Lett

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Abstract. Histone modifications of lysine residues have been implicated as having diagnostic and/or prognostic significance in numerous types of cancer. In the present study, the significance of the histone H3 methylation of lysine 4 (H3K4) and lysine 27 (H3K27) were investigated in endometrial cancer. Specifically, immunohistochemical analysis was used to detect the cellular expression levels of H3K27 trimethylation (H3K27me3), H3K4 trimethylation (H3K4me3) and H3K4 dimethylation (H3K4me2) in glandular epithelial tissues and stromal tissues. The association between the methylation levels of histone markers and clinicopathological parameters were analyzed. The results demonstrated that in epithelial cells, H3K4me2 and H3K4me3 exhibited the highest levels in endometrial cancer, followed by precancerous lesions and a normal endometrium. Low expression levels of H3K4me2 in glandular epithelium of endometrial cancer were significantly associated with a clinical early International Federation of Gynecology and Obstetrics stage (P= 0.006). For stromal tissues, the expression level of H3K27me3 in Type 1 endometrial cancer was significantly lower compared with that in the normal endometrium (P= 0.043) and precancerous lesions (P<0.001). The expression level of H3K4me2 was significantly lower in the stroma of Type 1 and 2 cancer compared within the normal endometrium (P= 0.005). A low H3K4me3 expression level in the stroma of endometrial cancer tissues was associated with P53-negativity (P= 0.032). In conclusion, the cellular expression levels of histone H3 methylation were differentially presented in glandular epithelial and stromal elements in endometrial tissues. A low expression level of activation marker H3K4me2 in glandular epithelium defined a subset of patients with early-stage endometrial adenocarcinoma and may have potential prognostic value.

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“…Given that supervised network analysis of DNA methylation data is a promising approach , it is therefore natural to also consider a three-way integration of DNA methylation and gene expression with a PPI network, as done by the FEM (Functional Epigenetic Modules) algorithm (Jiao et al 2014;Jones et al 2013) (Fig. 8.2).…”

Section: Systems-level Integration Of Dna Methylation and Gene Expresmentioning

confidence: 99%

“…Doing so in the context of cancer may not only reveal functional epigenetic drivers of cancer but may also shed light on specific signalling pathways or mechanisms which contribute to carcinogenesis. Indeed, a clear example of how such integration can pinpoint a cancer driver was a study performed in endometrial tumours, which using FEM identified a gene called HAND2 as causally implicated in the genesis of this cancer (Jiao et al 2014;Jones et al 2013;. The FEM algorithm is freely available from www.…”

Section: Systems-level Integration Of Dna Methylation and Gene Expresmentioning

confidence: 99%

“…The Illumina Infinium 450k chip is in fact still the technology of choice for studies from The Cancer Genome Atlas (TCGA) (see, e.g. Kandoth et al 2013) and epigenomewide association studies (EWAS) (Beck 2010;Rakyan et al 2011). For this reason, it has become important to assess which gene region represented on the 450k array is, at the DNAm level, most informative of gene expression.…”

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Systems Epigenomics and Applications to Ageing and Cancer

Teschendorff

2015

Translational Bioinformatics

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One way to view epigenomics is in terms of representing the software of living cells. It is increasingly recognised that complex diseases like cancer are not only driven by defects in the genetic machinery (i.e. the underlying hardware) but also by defects in the epigenome. However, to improve our understanding of how epigenomic aberrations may contribute to the causal development of diseases like cancer will require a systems-level epigenomics approach which integrates different omic data types together. In this chapter, we describe three systems-level statistical methods which have been successful in identifying novel biomarkers for ageing, for cancer risk and for early detection of cancer. In addition, these systems-level methods have provided us with substantial novel insights into systems-level aspects of carcinogenesis, which we also describe.

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Role of DNA Methylation and Epigenetic Silencing of HAND2 in Endometrial Cancer Development

Abstract: TB filled in by Laureen Please see later in the article for the Editors' Summary

Cited by 137 publications

References 44 publications

H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells

H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells

The expression and significance of histone lysine methylation in endometrial cancer

Systems Epigenomics and Applications to Ageing and Cancer

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