The Liggins Institute, University of Auckland, Auckland, New Zealand.
Hum Reprod. 2010 Nov;25(11):2859-69. doi: 10.1093/humrep/deq238. Epub 2010 Sep 7.
Decidualization, the differentiation of endometrial stromal cells is a crucial step for successful implantation of an embryo, development of the placenta and completion of pregnancy to term. Epigenetic mechanisms are thought to be strongly involved in the regulation of processes controlling implantation, placentation, organ formation and foetal growth. Recent studies suggest that decreased DNA methylation facilitates a receptive endometrium. Hence, the aim of this project was to compare the transcriptional profile changes induced by the inhibitor of DNA methylation, 5-Aza-2'-deoxycytidine (AZA) to the transcriptional changes that happen during decidualization.
When DNA methylation was inhibited in a human endometrial stromal cell (HESC) line with AZA, it resulted in the fibroblast-like stromal cells being transformed into decidual-like morphology after 9 days. Expression of both prolactin and insulin-like growth factor binding protein-1, the two established decidualization marker genes, were minimally up-regulated by AZA after 10 days of treatment. In a microarray of a three-way experiment between AZA-treated and oestradiol/progestin/cAMP-treated [medroxy-progesterone acetate (MPA)-mix] HESC and the untreated controls, we detected more than 1000 common genes that had a significant difference of expression compared with the controls. AZA-treated cells in the microarray significantly expressed 76 genes in common with the MPA-mix treated cells, and AZA treatment also differentially regulated 148 genes independently to that of MPA-mix treatment. The MPA-mix regulated at least 36 genes in the cell adhesion, extracellular matrix remodelling and RhoGTPase cytoskeletal reorganization pathway; AZA regulated 19 of these genes in common and 15 other RhoGTPase pathway genes.
AZA induced some decidualization-like responses of endometrial stromal cells independently of progestins or cAMP, possibly via the cytoskeletal reorganization pathway of the RhoGTPase family.
蜕膜化是子宫内膜基质细胞的分化，是胚胎成功着床、胎盘发育和足月妊娠的关键步骤。表观遗传机制被认为强烈参与调节控制着床、胎盘形成、器官形成和胎儿生长的过程。最近的研究表明，DNA 甲基化的减少促进了接受能力强的子宫内膜。因此，本项目的目的是比较 DNA 甲基化抑制剂 5-氮杂-2'-脱氧胞苷（AZA）诱导的转录谱变化与蜕膜化过程中发生的转录变化。
当 AZA 抑制人子宫内膜基质细胞（HESC）系中的 DNA 甲基化时，它导致纤维母细胞样基质细胞在 9 天后转变为蜕膜样形态。在经过 10 天的处理后，AZA 对催乳素和胰岛素样生长因子结合蛋白-1（两个已建立的蜕膜化标记基因）的表达仅有轻微的上调。在 AZA 处理和雌二醇/孕激素/cAMP 处理[醋酸甲羟孕酮（MPA）混合]HESC 与未处理对照的三向实验的微阵列中，我们检测到 1000 多个与对照相比表达差异显著的共同基因。在微阵列中，与 MPA 混合处理的细胞相比，AZA 处理的细胞有 76 个基因显著表达，并且 AZA 处理还独立于 MPA 混合处理调节了 148 个基因。MPA 混合处理调节了细胞黏附、细胞外基质重塑和 RhoGTPase 细胞骨架重排途径中的至少 36 个基因；AZA 共同调节了其中 19 个基因，还有 15 个其他 RhoGTPase 途径基因。
AZA 独立于孕激素或 cAMP 诱导子宫内膜基质细胞的一些蜕膜化样反应，可能通过 RhoGTPase 家族的细胞骨架重排途径。
Zotero 插件