Alternative roles for oxidized mCs and TETs

Cimmino, Luisa; Aifantis, Iannis

doi:10.1016/j.gde.2016.11.003

Cited by 29 publications

(26 citation statements)

References 86 publications

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“…Levels of genomic 5mC and 5hmC are substantially reduced in cancer tissues. These changes are implicated in compromised genomic integrity and tumorigenesis . Therefore, we investigated whether reductions in 5mC and 5hmC levels were involved in tumor increase in F2 males following gestational arsenic exposure of F0 females.…”

Section: Resultsmentioning

confidence: 99%

“…Those methylation changes are related to adverse health effects including cancer . Total levels of 5mC and 5hmC are known to be reduced in cancer tissues, and can compromise genomic integrity and lead to tumor growth . In tumor tissues, site‐specific hypermethylation of cytosines have also been observed in the promoter regions of suppressor genes and are considered to contribute to tumor formation …”

Section: Introductionmentioning

confidence: 99%

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DNA methylation changes involved in the tumor increase in F2 males born to gestationally arsenite‐exposed F1 male mice

et al. 2019

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Multigenerational adverse effects from the environment such as nutrition and chemicals are among important concerns in environmental health issues. Previously, we have found that arsenite exposure of only F0 females during their pregnancy increases hepatic tumors in the F2 males in C3H mice. In the current study, we investigated the association of DNA methylation with the hepatic tumor increase in the F2 males of the arsenite group. Reduced‐representation bisulfite sequencing analysis newly identified that DNA methylation levels of regions around the transcriptional start sites of Tmem54 and Cd74 were decreased and the expression of these genes were significantly increased in the hepatic tumors of F2 males of the arsenite group. The associations between DNA methylation in these regions and gene expression changes were confirmed by treatment of murine hepatoma cell lines and hepatic stellate cell line with 5‐aza‐2′‐deoxycytidine. Overexpression of Cd74 in Hepa1c1c7 cells increased Trib3 expression and suppressed the expression of tumor suppressor genes Id3 and Atoh8. Human database analysis using the Cancer Genome Atlas indicated that TMEM54, CD74, and TRIB3 were significantly increased and that ATOH8 was decreased in hepatocellular carcinoma. The data also showed that high expression of TMEM54 and TRIB3 and low expression of ATOH8 were associated with poor survival. These results suggested that an increase in Tmem54 and Cd74 expression via DNA methylation reduction was involved in the tumor increase in the F2 male offspring by gestational arsenite exposure of F0 females. This study also suggested that genes downstream of Cd74 were involved in tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DNA methylation changes involved in the tumor increase in F2 males born to gestationally arsenite‐exposed F1 male mice

et al. 2019

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“…5hmC and TET proteins are regarded as tumour supressors and defects in active DNA demethylation pathways may be a cause of malignancy . The loss of 5hmC as the consequence of mutations and decreased activity in TETs has been documented in multiple tumour tissues including a subset of hepatocellular carcinomas .…”

Section: Discussionmentioning

confidence: 99%

“…5‐hydroxymethylcytosine (5hmC), an oxidised form of 5‐methylcytosine generated by 10‐11 translocation (TET) proteins, has emerged as an important epigenetic marker that reflects the status of cellular epigenetic pathways important for development, ageing and diseases . Dysregulation of epigenetic pathways, including mutations to TET proteins, has been previously implicated in the pathogenesis of human cancers . Recent studies have reported that the levels of 5hmC and TET proteins are substantially decreased in human cancers including melanoma, glioma, gastric cancers, and renal cell carcinomas .…”

Section: Introductionmentioning

confidence: 99%

Loss of 5‐hydroxymethylcytosine immunohistochemical expression is a useful diagnostic aid for distinguishing hepatocellular carcinoma in cytology fine needle aspiration specimens

2019

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Objective: Disruption of the DNA methylation pathway involving 5-hydroxymethylcytosine (5hmC) has been implicated in hepatic tumour development. The aim of this study was to investigate the expression of 5hmC in malignant and benign hepatic mass lesions and evaluate the diagnostic utility of deficient 5hmC expression in hepatocellular carcinoma (HCC). Methods:Our study consisted of 48 fine needle aspiration (FNA) cytological cases (30 cases positive for HCC, 18 cases negative for malignancy) and 39 liver resection specimens (30 HCCs and nine hepatic adenomas [HAs]). A 5hmC immunohistochemistry score (range 0-9) was calculated by multiplying the percentage (0 = no staining; 1 = 1%-10%; 2 = 11%-50%; 3 = 51%-100%) and intensity scores (0-3+). A score of ≤2 was considered deficient for 5hmC. Results:In resection specimens, 5hmC expression was deficient in 90% of HCC cases. Surrounding cirrhotic nodules and 78% of HA cases exhibited intact 5hmC expression. In FNA cytological specimens, expression of 5hmC was deficient in nearly all cases of HCC (96.7%, 29/30 cases). Admixed benign hepatocytes exhibited predominantly intact expression of 5hmC with moderate to strong nuclear staining in the majority of the benign hepatocytes. 5hmC was strongly expressed by endothelial cells, lymphocytes and neutrophils in the background. Many 5hmC-negative HCC clusters were highlighted by characteristic endothelial wrapping with strong 5hmC expression in the endothelial cells.Conclusions: 5hmC can serve as an important diagnostic tool for the diagnosis of HCC by aiding in the distinction of HCC from HA or cirrhotic nodules in both liver resection and FNA specimens. K E Y W O R D S5-hydroxymethylcytosine, cytology, hepatocellular carcinoma, immunohistochemistry

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“…Indeed, 3 groups have observed such metaphase chromosomes in mouse and human ESCs, human induced pluripotent stem cells (iPSCs), and female human somatic cells derived from iPSCs [Szulwach et al, 2011;Kubiura et al, 2012;Bogomazova et al, 2014]. The biological function of 5hmC strand bias is an open and intriguing question, and it has been suggested that it may be involved in the regulation of asymmetric gene expression and/or DNA repair [Cimmino and Aifantis, 2017].…”

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confidence: 99%

Inter-Cell and Inter-Chromosome Variability of 5-Hydroxymethylcytosine Patterns in Noncultured Human Embryonic and Extraembryonic Cells

Efimova

Pendina

Krapivin

et al. 2018

Cytogenet Genome Res

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5-hydroxymethylcytosine (5hmC) is an oxidative derivative of 5-methylcytosine (5mC). Recent studies have revealed a sharp difference in the levels of 5hmC in 2 opposite DNA strands of a given chromosome and a chromosome-wide cell-to-cell variability in mammalian cells. This asymmetric 5hmC distribution was found in cultured cells, which may not fully mimic in vivo epigenetic processes. We have checked whether inter-chromosome and inter-cell variability of 5hmC patterns is typical for noncultured human cells. Using indirect immunofluorescence, we analyzed the localization of 5hmC and its co-distribution with 5mC on direct preparations of mitotically active cells from human embryonic lung and chorionic cytotrophoblast samples. We demonstrated 3 types of chromosomes according to the 5hmC accumulation pattern: hydroxymethylated (5hmC in both sister chromatids), hemihydroxymethylated (5hmC in only 1 sister chromatid), and nonhydroxymethylated ones. Each accumulation type was not specific to any particular chromosome, resulting in different 5hmC patterns between homologous chromosomes, among chromosomes within each metaphase plate, among metaphases in one tissue, and between the tissues. The 5mC distribution was stable: chromosomes were methylated in R-bands and, especially in embryonic lung cells, in the heterochromatic regions 1q12, 9q12, and 16q11.2. Our results provide the first evidence of inter-cell and inter-chromosome variability of 5hmC patterns in human noncultured embryonic and extraembryonic cells.

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Alternative roles for oxidized mCs and TETs

Cited by 29 publications

References 86 publications

DNA methylation changes involved in the tumor increase in F2 males born to gestationally arsenite‐exposed F1 male mice

DNA methylation changes involved in the tumor increase in F2 males born to gestationally arsenite‐exposed F1 male mice

Loss of 5‐hydroxymethylcytosine immunohistochemical expression is a useful diagnostic aid for distinguishing hepatocellular carcinoma in cytology fine needle aspiration specimens

Inter-Cell and Inter-Chromosome Variability of 5-Hydroxymethylcytosine Patterns in Noncultured Human Embryonic and Extraembryonic Cells

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