Disease-dependent Differently Methylated Regions (D-DMRs) of DNA are Enriched on the X Chromosome in Uterine Leiomyoma

Maekawa, Ryo; Yagi, Shusuke; Ohgane, Jun; Yamagata, Yuriko; Asada, Hiromi; Shiota, Kunio

doi:10.1262/jrd.11-035a

Cited by 32 publications

(32 citation statements)

References 42 publications

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“…6A and B), suggesting that miR-452 is likely to be co-transcribed with GABRE mRNA. Promoter methylation has been reported to control GABRE expression in gastric cancer and uterine leiomyoma (23, 24). Therefore, we investigated whether the reduced miR-452 in gliomas was a result of promoter hypermethylation.…”

Section: Resultsmentioning

confidence: 99%

Downregulation of miR-452 Promotes Stem-Like Traits and Tumorigenicity of Gliomas

Liu

Chen

et al. 2013

Clinical Cancer Research

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Purpose miR-452 is reported to be required for neural crest stem cell differentiation during neural crest development. However, the biological role of miR-452 in gliomas remains unclear. The aim of the present study was to evaluate the effect of miR-452 on the stem-like properties and tumorigenesis of glioma cells. Experimental Design The expression of miR-452 was examined in glioma cells and glioma tissues using real-time PCR. The effects of miR-452 on stem-like traits and tumorigenesis were investigated in vitro and in vivo using patient-derived glioma cells and glioma cell lines. Western blotting and luciferase reporter assays were performed to examine the negative regulation of Bmi-1, LEF1 and TCF4 by miR-452. The methylation of the miR-452 promoter region was examined by bisulfite genomic sequencing PCR. Results miR-452 was markedly downregulated in glioma cells and clinical glioma tissues. miR-452 levels inversely correlated with WHO grades and patient survival. miR-452 directly targeted and suppressed multiple stemness regulators, including Bmi-1, LEF1 and TCF4, resulting in reduced stem-like traits and tumorigenesis of glioma cells in vitro and in vivo. Furthermore, we demonstrated that downregulation of miR-452 in gliomas was caused by hypermethylation of its promoter region. Conclusions Downregulation of miR-452 plays an important role in promoting the stem-like traits and tumorigenesis of gliomas and may represent a novel prognostic biomarker and therapeutic target for the disease.

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Section: Resultsmentioning

confidence: 99%

Downregulation of miR-452 Promotes Stem-Like Traits and Tumorigenicity of Gliomas

Liu

Chen

et al. 2013

Clinical Cancer Research

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“…However, the other study was insufficient to identify differences in DNA methylation, which could be due to the small number of samples investigated [15]–[16]. Here, we report the first genome-wide analysis of differential DNA-methylation and mRNA expression in uterine leiomyoma and adjacent normal myometrial tissues from 18 matched pairs, all from African American subjects to limit biological heterogeneity, and avoid epigenetic variations among ethnic groups.…”

Section: Discussionmentioning

confidence: 98%

Genome-Wide DNA Methylation Indicates Silencing of Tumor Suppressor Genes in Uterine Leiomyoma

et al. 2012

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BackgroundUterine leiomyomas, or fibroids, represent the most common benign tumor of the female reproductive tract. Fibroids become symptomatic in 30% of all women and up to 70% of African American women of reproductive age. Epigenetic dysregulation of individual genes has been demonstrated in leiomyoma cells; however, the in vivo genome-wide distribution of such epigenetic abnormalities remains unknown.Principal FindingsWe characterized and compared genome-wide DNA methylation and mRNA expression profiles in uterine leiomyoma and matched adjacent normal myometrial tissues from 18 African American women. We found 55 genes with differential promoter methylation and concominant differences in mRNA expression in uterine leiomyoma versus normal myometrium. Eighty percent of the identified genes showed an inverse relationship between DNA methylation status and mRNA expression in uterine leiomyoma tissues, and the majority of genes (62%) displayed hypermethylation associated with gene silencing. We selected three genes, the known tumor suppressors KLF11, DLEC1, and KRT19 and verified promoter hypermethylation, mRNA repression and protein expression using bisulfite sequencing, real-time PCR and western blot. Incubation of primary leiomyoma smooth muscle cells with a DNA methyltransferase inhibitor restored KLF11, DLEC1 and KRT19 mRNA levels.ConclusionsThese results suggest a possible functional role of promoter DNA methylation-mediated gene silencing in the pathogenesis of uterine leiomyoma in African American women.

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“…We detected similar levels of XIST expression in the myometrium and leiomyoma [17]. Some other molecules have been implicated in XCI, including SATB1 and HNRNPU , which function upstream of PRC in the XCI pathway, and SMCHD1 , which functions downstream of PRC [25,26,27,28,29].…”

mentioning

confidence: 82%

“…We recently found that the aberrant DNA methylation occurs throughout the genome in uterine leiomyomas [15,16,17]. We identified 120 genes that are differently methylated and expressed between the leiomyoma and the adjacent normal myometrium, including a number of cancer-related genes [18].…”

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confidence: 99%

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Potential Mechanisms of Aberrant DNA Hypomethylation on the X Chromosome in Uterine Leiomyomas

Sato

Maekawa

Yamagata

et al. 2014

Journal of Reproduction and Development

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Abstract. We recently found that aberrant DNA hypomethylation is more common on the X chromosome than on other chromosomes in uterine leiomyomas by genome-wide DNA methylation profiling. To investigate the mechanism of aberrant hypomethylation on the X chromosome in uterine leiomyomas, we analyzed methylome and transcriptome data from three cases of leiomyomas and the adjacent myometrium. We found that eleven of the aberrantly hypomethylated genes on the X chromosome were common to the three cases. None of these 11 genes were transcriptionally upregulated in the leiomyoma. However, one of them, TSPYL2, was hypomethylated in 68% of multiple leiomyoma specimens. The incidence of aberrant hypomethylation of TSPYL2 was comparable to that of the MED12 mutation (68%), which is known to be detected at a high frequency in uterine leiomyomas. We also analyzed the aberration of the X chromosome inactivation (XCI) mechanism in uterine leiomyomas. Hypomethylation was not enriched in the imprinted genes, suggesting that dysfunction of polycomb repressive complexes is not involved in the aberrant hypomethylation on the X chromosome. The expression analysis of XCI-related genes revealed that the XIST and SATB1 expression was downregulated in 36% and 46% of 11 leiomyoma specimens, respectively, while the HNRNPU and SMCHD1 expression was not altered. In conclusion, the aberration of XCI-related genes such as SATB1 or XIST may be involved in aberrant hypomethylation on the X chromosome in a certain population of the patients with uterine leiomyomas. TSPYL2 of the aberrantly hypomethylated genes on the X chromosome can be used as a biomarker of uterine leiomyomas.

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Disease-dependent Differently Methylated Regions (D-DMRs) of DNA are Enriched on the X Chromosome in Uterine Leiomyoma

Cited by 32 publications

References 42 publications

Downregulation of miR-452 Promotes Stem-Like Traits and Tumorigenicity of Gliomas

Downregulation of miR-452 Promotes Stem-Like Traits and Tumorigenicity of Gliomas

Genome-Wide DNA Methylation Indicates Silencing of Tumor Suppressor Genes in Uterine Leiomyoma

Potential Mechanisms of Aberrant DNA Hypomethylation on the X Chromosome in Uterine Leiomyomas

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