Developmental Reprogramming of Myometrial Stem Cells by Endocrine Disruptor Linking to Risk of Uterine Fibroids [RNA-Seq]

We report that developmental exposure to the endocrine disrupting chemical (EDC) diethylstilbestrol increases the estrogen action in myometrial stem cells (MMSCs), the origin from which UFs originate. The expression of reprogrammed estrogen responsive genes (ERGs) is driven by activated mixed lineage leukemia protein-1 (MLL1) in MMSCs. Deactivation of MLL1 reverses reprogramming of ERG expression. In addition, upregulation of ERGs occurs via DNA hypomethylation mechanism. Furthermore, the secretome of reprogrammed MMSCs enhances the proliferation of differentiated myometrial cells through activation of β-catenin signaling. This work identifies epigenetic mechanisms of MLL1/DNA methyltransferase- mediated MMSC reprogramming, and EDC exposure epigenetically targets MMSCs and imparts a hormonal imprint on the ERGs resulting in a “hyper-estrogenized” phenotype and increased hormone-dependent risk of UFs.本研究报道，发育期暴露于内分泌干扰物（endocrine disrupting chemical, EDC）己烯雌酚，可增强子宫肌层干细胞（myometrial stem cells, MMSCs）中的雌激素活性——而UFs正是起源于这类细胞。重编程雌激素应答基因（estrogen responsive genes, ERGs）的表达由MMSCs中激活的混合谱系白血病蛋白1（mixed lineage leukemia protein-1, MLL1）所驱动。使MLL1失活可逆转ERGs的表达重编程过程。此外，ERGs的上调通过DNA低甲基化机制实现。进一步研究发现，重编程后的MMSCs的分泌组（secretome）可通过激活β-连环蛋白信号通路（β-catenin signaling），促进分化型子宫肌层细胞的增殖。本研究阐明了MLL1/DNA甲基转移酶（DNA methyltransferase）介导的MMSCs重编程的表观遗传机制，证实EDC暴露可通过表观遗传靶向MMSCs，并对ERGs施加激素印记，最终产生“高雌激素化”表型，提升UFs的激素依赖性患病风险。