The 5'-end transitional CpGs between the CpG islands and retroelements are hypomethylated in association with loss of heterozygosity in gastric cancers

Kim, Young‐Ho; Hong, Seung‐Jin; Jung, Yuchae; Kim, Sung-Ja; Seo, Eun-Joo; Choi, Sae Kyung; Rhyu, Mun-Gan

doi:10.1186/1471-2407-6-180

Cited by 13 publications

(33 citation statements)

References 39 publications

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“…The transitional-CpG sites of the stomach-specific genes ( PGA5 and PGC ) [22], the mucosa-healing genes ( TFF1 and TFF2 ) [23], the cancer-related genes ( CDH1 , MLH1 , PPARG , CDKN2A and RUNX3 ) [15,24-27], and the non-gastric genes ( ARRDC4 , DUSP6 , TRAPPC2L , MSLN and KRT6A ) [28-32] were selected (Table 1). The MSP sites, sequences, and conditions are shown in Additional File 1.…”

Section: Methodsmentioning

confidence: 99%

The overmethylated genes in Helicobacter pylori-infected gastric mucosa are demethylated in gastric cancers

Hong

Jeon

et al. 2010

BMC Gastroenterol

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BackgroundThe transitional-CpG sites between weakly methylated genes and densely methylated retroelements are overmethylated in the gastric mucosa infected with Helicobacter pylori (H. pylori) and they are undermethylated in the gastric cancers depending on the level of loss of heterozygosity (LOH) events. This study delineated the transitional-CpG methylation patterns of CpG-island-containing and -lacking genes in view of the retroelements.MethodsThe transitional-CpG sites of eight CpG-island-containing genes and six CpG-island-lacking genes were semi-quantitatively examined by performing radioisotope-labelling methylation-specific PCR under stringent conditions. The level of LOH in the gastric cancers was estimated using the 40 microsatellite markers on eight cancer-associated chromosomes. Each gene was scored as overmethylated or undermethylated based on an intermediate level of transitional-CpG methylation common in the H. pylori-negative gastric mucosa.ResultsThe eight CpG-island genes examined were overmethylated depending on the proximity to the nearest retroelement in the H. pylori-positive gastric mucosa. The six CpG-island-lacking genes were similarly methylated in the H. pylori-positive and -negative gastric mucosa. In the gastric cancers, long transitional-CpG segments of the CpG-island genes distant from the retroelements remained overmethylated, whereas the overmethylation of short transitional-CpG segments close to the retroelements was not significant. Both the CpG-island-containing and -lacking genes tended to be decreasingly methylated in a LOH-level-dependent manner.ConclusionsThe overmethylated genes under the influence of retroelement methylation in the H. pylori-infected stomach are demethylated in the gastric cancers influenced by LOH.

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Section: Methodsmentioning

confidence: 99%

The overmethylated genes in Helicobacter pylori-infected gastric mucosa are demethylated in gastric cancers

Hong

Jeon

et al. 2010

BMC Gastroenterol

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“…Although the CpG islands are consistently unmethylated in most tissue types, some transitional CpG sites between retroelements and promoters are methylated to various levels in a tissue‐specific manner [Kang et al, 2006]. Methylation‐variable CpGs associated with the retroelements could be found near the boundaries of CpG islands and at the nonisland CpG sites close to the transcription start sites of the genes lacking CpG islands [Kang et al, 2006; Kim et al, 2006], which are expected to influence the phenotype plasticity of mesenchymal cells through the DNA methylation‐dependent mechanism.…”

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confidence: 99%

“…Tissue‐specific transitional methylation between the transcription start site and the nearest retroelements was previously described for the mesenchyme‐related (RUNX2) and ‐unrelated (RUNX3) genes as well as the housekeeping genes (CDKN2A and MLH1) [Kang et al, 2006; Kim et al, 2006]. This study examined tissue‐specific transitional methylation and gene expression in the BMSC and ATSC under the differentiation induction and oxidative stress.…”

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Transitional CpG methylation between promoters and retroelements of tissue‐specific genes during human mesenchymal cell differentiation

Kang

Kim

Jung

et al. 2007

J of Cellular Biochemistry

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In general, methylation of the promoter regions is inversely correlated with gene expression. The transitional CpG area between the promoter-associated CpG islands and the nearby retroelements is often methylated in a tissue-specific manner. This study analyzed the relationship between gene expression and the methylation of the transitional CpGs in two human stromal cells derived from the bone marrow (BMSC) and adipose tissue (ATSC), both of which have a multilineage differentiation potential. The transitional CpGs of the osteoblast-specific (RUNX2 and BGLAP), adipocyte-specific (PPARgamma2), housekeeping (CDKN2A and MLH1), and mesenchyme-unrelated (RUNX3) genes were examined by methylation-specific PCR. The expression of each gene was measured using reverse-transcription PCR analysis. The RUNX2, BGLAP, and CDKN2A genes in the BMSC, and the PPARgamma2 gene in the ATSC exhibited hypomethylation of the transitional CpGs along with the strong expression. The CpG island of RUNX3 gene not expressed in both BMSC and ATSC was hypermethylated. Transitional hypomethylation of the MLH1 gene was accompanied by the higher expression in the BMSC than in the ATSC. The weakly methylated CpGs of the PPARgamma2 gene in the BMSC became hypomethylated along with the strong expression during the osteoblastic differentiation. There were no notable changes in the transitional methylation and expression of the genes other than PPARgamma2 after the differentiation. Therefore, the transitional methylation and gene expression established in mesenchymal cells tend to be consistently preserved under the induction of differentiation. Weak transitional methylation of the PPARgamma2 gene in the BMSC suggests a methylation-dependent mechanism underlying the adiopogenesis of bone marrow.

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“…ALU-mediated sequence insertions can also occur through retrotransposition, whereby ALU elements are reverse transcribed and randomly inserted back into the genome [3, 4] Retrotransposition rates are thought to increase over time following age-related hypomethylation of ALU elements[14–16]; however, the retrotransposition rates of older subfamilies, like ALU-Sx and ALU-J , are predicted to be far lower than that of younger subfamilies[17–19]. Interestingly, age-related hypomethylation of ALU elements has been linked to osteoporosis, obesity, and gastric and lung cancer[15, 16, 20–22]. Importantly, clonal selection and expansion of mutant genomes in proliferative cell types might amplify any maladaptive effects within a tissue following an ALU-mediated mutational event[1, 23, 24].…”

Section: Introductionmentioning

confidence: 99%

Age-Associated ALU Element Instability in White Blood Cells Is Linked to Lower Survival in Elderly Adults: A Preliminary Cohort Study

et al. 2017

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BackgroundALU element instability could contribute to gene function variance in aging, and may partly explain variation in human lifespan.ObjectiveTo assess the role of ALU element instability in human aging and the potential efficacy of ALU element content as a marker of biological aging and survival.DesignPreliminary cohort study.MethodsWe measured two high frequency ALU element subfamilies, ALU-J and ALU-Sx, by a single qPCR assay and compared ALU-J/Sx content in white blood cell (WBCs) and skeletal muscle cell (SMCs) biopsies from twenty-three elderly adults with sixteen healthy sex-balanced young adults; all-cause survival rates of elderly adults predicted by ALU-J/Sx content in both tissues; and cardiovascular disease (CVD)- and cancer-specific survival rates of elderly adults predicted by ALU-J/Sx content in both tissues, as planned subgroup analyses.ResultsWe found greater ALU-J/Sx content variance in WBCs from elderly adults than young adults (P < 0.001) with no difference in SMCs (P = 0.94). Elderly adults with low WBC ALU-J/Sx content had worse four-year all-cause and CVD-associated survival than those with high ALU-J/Sx content (both P = 0.03 and hazard ratios (HR) ≥ 3.40), while WBC ALU-J/Sx content had no influence on cancer-associated survival (P = 0.42 and HR = 0.74). SMC ALU-J/Sx content had no influence on all-cause, CVD- or cancer -associated survival (all P ≥ 0.26; HR ≤ 2.07).ConclusionsThese initial findings demonstrate that ALU element instability occurs with advanced age in WBCs, but not SMCs, and imparts greater risk of all-cause mortality that is likely driven by an increased risk for CVD and not cancer.

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The 5'-end transitional CpGs between the CpG islands and retroelements are hypomethylated in association with loss of heterozygosity in gastric cancers

Cited by 13 publications

References 39 publications

The overmethylated genes in Helicobacter pylori-infected gastric mucosa are demethylated in gastric cancers

The overmethylated genes in Helicobacter pylori-infected gastric mucosa are demethylated in gastric cancers

Transitional CpG methylation between promoters and retroelements of tissue‐specific genes during human mesenchymal cell differentiation

Age-Associated ALU Element Instability in White Blood Cells Is Linked to Lower Survival in Elderly Adults: A Preliminary Cohort Study

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