Developmental Reprogramming of Myometrial Stem Cells by Endocrine Disruptor Linking to Risk of Uterine Fibroids [ChIP-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.本研究表明，发育期暴露于内分泌干扰物（endocrine disrupting chemical, EDC）己烯雌酚（diethylstilbestrol），可提升子宫肌层干细胞（myometrial stem cells, MMSCs）内的雌激素活性；而此类细胞正是子宫肌瘤（UFs）的起源细胞。重编程雌激素应答基因（estrogen responsive genes, ERGs）的表达，由MMSCs中活化的混合谱系白血病蛋白1（mixed lineage leukemia protein-1, MLL1）所驱动。MLL1的失活可逆转ERGs的表达重编程。此外，ERGs的上调可通过DNA低甲基化机制实现。进一步而言，重编程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，证实内分泌干扰物可通过表观遗传靶向调控MMSCs，并在ERGs上留下激素印记，最终形成"hyper-estrogenized"表型，同时提升激素依赖性子宫肌瘤的患病风险。