Ten-Eleven Translocation Genes are Downregulated in Endometriosis.
Ten-Eleven Translocation Genes are Downregulated in Endometriosis.
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DOI：
10.2174/1566524016666160225153844
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发表时间：
2016-02
影响因子：
2.5
通讯作者：
F. J. Roca;Holli A. Loomans;A. Wittman;Chad J. Creighton;Shannon M. Hawkins
中科院分区：
文献类型：
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作者：
F. J. Roca;Holli A. Loomans;A. Wittman;Chad J. Creighton;Shannon M. Hawkins
我们先前对子宫内膜瘤的全基因组表达分析表明，10-11个易位基因(TET1、TET2和TET3)失调，参与将5-甲基胞嘧啶转化为5-羟甲基胞嘧啶(5-HMC)。本研究的目的是验证Tet基因在人子宫内膜间质成纤维细胞(HESF)体外蜕膜形成过程中异位内膜、在位内膜和原代培养中的表达，并对子宫内膜异位症患者体内5-HMC水平进行定量。在妇科手术时采集血液、在位子宫内膜和子宫内膜异位组织。HESF培养自无(HESF-对照)和有子宫内膜异位症(HESF-Endo)的在位子宫内膜，并进行体外蜕膜化。用ELISA法测定血液和组织中5-HMC的绝对量。TET1、TET2和TET3在子宫内膜异位症患者中的表达低于非子宫内膜异位症对照在位内膜。令人惊讶的是，异位内膜中5-HMC的总体含量高于对照在位内膜，而子宫内膜异位症患者血液中5-HMC的含量显著低于非内异症患者。TET1、TET2和TET3在非蜕膜化HESFENDO中的表达降低。在体外蜕膜化后，对照HESF显示TET3的表达减少，而蜕膜化的HESF-Endo在TET1、TET2或TET3的表达没有统计学意义的变化。这些结果表明，Tet基因在异位内膜和HESF-Endo中表达下调，首次提示Tet基因在子宫内膜异位症中起作用。子宫内膜异位症组织中高水平的5-HMC提示在这些组织中存在独特的表观遗传调控。
Our previous whole genome expression analysis of endometriomas suggested dysregulation of the ten-eleven translocation genes (TET1, TET2, and TET3), involved in converting 5- methylcytosine to 5-hydroxymethylcytosine (5-hmC). The objective of this study was to validate the expression of TET genes in ectopic and eutopic endometrium and in primary cultures of human endometrial stromal fibroblasts (HESF) during in vitro decidualization and to quantify 5-hmC levels in patients with endometriosis. Blood, eutopic endometrium, and endometriotic tissues were collected at time of gynecologic surgery. HESF cultures were created from eutopic endometrium of women without (HESF-CONTROL) and with endometriosis (HESF-ENDO) and underwent in vitro decidualization. Genomic DNA from blood and tissues underwent quantification of the absolute amount of 5-hmC using ELISA. The expression of TET1, TET2, and TET3 was decreased in endometriosis compared to non-endometriosis control eutopic endometrium. Surprisingly, the global amount of 5-hmC was higher in ectopic endometrium than control eutopic endometrium, while genomic DNA from blood of women with endometriosis contained statistically significantly less 5-hmC than women without endometriosis. Expression of TET1, TET2, and TET3 was decreased in non-decidualized HESFENDO. Upon in vitro decidualization, control HESF showed decreased expression of TET3, while decidualized HESF-ENDO showed no statistically significant change in expression of TET1, TET2, or TET3. These results indicate that the TET genes are downregulated in ectopic endometrium and in HESF-ENDO, and suggest for the first time that TET genes play a role in endometriosis. High global amounts of 5-hmC in endometriotic tissues suggest unique epigenetic regulation in these tissues.