Disease-dependent Differently Methylated Regions (D-DMRs) of DNA are Enriched on the X Chromosome in Uterine Leiomyoma
Disease-dependent Differently Methylated Regions (D-DMRs) of DNA are Enriched on the X Chromosome in Uterine Leiomyoma
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DOI：
10.1262/jrd.11-035a
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发表时间：
2011-10-01
影响因子：
1.8
通讯作者：
Shiota, Kunio
中科院分区：
文献类型：
--
作者：
Maekawa, Ryo;Yagi, Shintaro;Shiota, Kunio
子宫平滑肌瘤是女性最常见的良性肿瘤。虽然在平滑肌瘤中没有发现相关的基因突变，但它们代表了一种具有不可逆症状的进行性疾病。为了表征子宫平滑肌瘤的表观遗传特征，我们使用限制性标签介导扩增（D-REAM）技术对平滑肌瘤和正常子宫肌的配对样本进行了基于微阵列的DNA甲基化分析。在平滑肌瘤中，我们发现了463个低甲基化基因和318个高甲基化基因的异常DNA甲基化状态。尽管这些变化发生在所有染色体上，但异常低甲基化基因优先位于X染色体上。利用6例子宫切除术患者的正常子宫肌层和平滑肌瘤配对样本，甲基化敏感定量实时PCR发现14个共有的DNA低甲基化状态异常的X染色体基因（FAM9A、CPXCR1、CXORF45、TAF1、NXF5、VBP1、GABRE、DDX53、FHL1、BRCC3、DMD、GJB1、AP1S2和PCDH11X）和1个高甲基化位点（HDAC8）。参与X染色体失活的XIST基因在正常子宫肌瘤和平滑肌瘤中表达相同，说明X染色体表观遗传异常并非由XIST基因表达异常引起。基于这些数据，子宫平滑肌瘤的一个独特的表观遗传特征已经出现。14个低甲基化位点和1个高甲基化位点为了解平滑肌瘤的分子发病机制提供了有价值的生物标志物。
Uterine leiomyoma is the most common benign tumor in women. Although responsible gene mutations have not been found in leiomyomas, they represent a progressive disease with irreversible symptoms. To characterize epigenetic features of uterine leiomyomas, the DNA methylation status of a paired sample of leiomyoma and normal myometrium was subjected to a microarray-based DNA methylation analysis with restriction tag-mediated amplification (D-REAM). in the leiomyoma, we identified an aberrant DNA methylation status for 463 hypomethylated and 318 hypermethylated genes. Although these changes occurred on all chromosomes, aberrantly hypomethylated genes were preferentially located on the X chromosome. Using paired samples of normal myometrium and leiomyoma from 6 hysterectomy patients, methylation-sensitive quantitative real-time PCR revealed 14 shared X chromosome genes with an abnormal DNA hypomethylation status (FAM9A, CPXCR1, CXORF45, TAF1, NXF5, VBP1, GABRE, DDX53, FHL1, BRCC3, DMD, GJB1, AP1S2 and PCDH11X) and one hypermethylated locus (HDAC8). Expression of XIST, which is involved in X chromosome inactivation, was equivalent in the normal myometrium and leiomyoma, indicating that the epigenetic abnormality on the X chromosome did not result from aberration of XIST gene expression. Based on these data, a unique epigenetic signature for uterine leiomyomas has emerged. The 14 hypomethylated and one hypermethylated loci provide valuable biomarkers for understanding the molecular pathogenesis of leiomyoma.