Potential mechanisms of aberrant DNA hypomethylation on the x chromosome in uterine leiomyomas.
Potential mechanisms of aberrant DNA hypomethylation on the x chromosome in uterine leiomyomas.
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DOI：
10.1262/jrd.2013-095
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发表时间：
2014-03-07
期刊：
影响因子：
--
通讯作者：
Sugino N
中科院分区：
文献类型：
--
作者：
Sato S;Maekawa R;Yamagata Y;Asada H;Tamura I;Lee L;Okada M;Tamura H;Sugino N
我们最近通过全基因组DNA甲基化分析发现，子宫肌瘤中X染色体上的异常DNA低甲基化比其他染色体上更常见。为了研究子宫肌瘤X染色体异常低甲基化的机制，我们分析了三例子宫肌瘤及其邻近肌层的甲基化组和转录组数据。我们发现X染色体上的11个异常低甲基化基因在这三个病例中是共同的。这11个基因中没有一个在平滑肌瘤中转录上调。然而，其中之一，TSPYL2，在68%的多发性平滑肌瘤标本中低甲基化。TSPYL2异常低甲基化的发生率与MED12突变的发生率（68%）相当，MED12突变在子宫平滑肌瘤中的检出率很高。我们还分析了子宫肌瘤X染色体失活（XCI）机制的畸变。低甲基化并没有丰富的印记基因，这表明polycomb抑制复合物的功能障碍是不参与异常低甲基化的X染色体。XCI相关基因的表达分析显示，XIST和SATB 1的表达分别在36%和46%的11例平滑肌瘤标本中下调，而HNRNPU和SMCHD 1的表达没有改变。结论：XCI相关基因如SATB 1或XIST的异常可能与子宫肌瘤患者X染色体异常低甲基化有关。X染色体上异常低甲基化基因TSPYL2可作为子宫肌瘤的生物标志物。
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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