当组织和器官正在生长发育的阶段，它们对环境影响非常敏感，但目前尚不清楚这段时间内的暴露如何导致表观基因组的改变，增加了子宫肌瘤等激素相关疾病的风险。通过RNA-seq、ChIP-seq、RRBS、功能增强/减弱分析和荧光素酶活性分析，在培养中和Eker大鼠模型中对母细胞干细胞（MMSCs）进行了发育重编程的研究，该细胞被认为是子宫肌瘤的可能起源。当暴露于内分泌干扰化学物质（EDC）二乙基雌酚时，发现MMSCs经历了其雌激素响应转录组的重编程。在MMSCs中，重编程的基因称为雌激素响应基因（ERGs），并通过混合祖细胞白血病蛋白-1（MLL1）和DNA低甲基化机制被激活。此外，我们观察到，在EDC发育暴露后，经常遭受自然类固醇物质暴露的Eker大鼠的MMSCs中，ERGs的表达显著升高，从而增强了雌激素的活性。我们的研究确定了MLL1/DNA低甲基化介导的MMSC重编程的表观遗传机制。EDC的暴露通过表观遗传方式靶向MMSCs，导致一部分ERGs的表达持久性改变，给ERGs打上激素印记，使其呈现出“过度雌激素”表型，并增加了激素依赖性子宫肌瘤的风险。© 2023. 作者。

The stage, when tissues and organs are growing, is very vulnerable to environmental influences, but it's not clear how exposure during this time causes changes to the epigenome and increases the risk of hormone-related illnesses like uterine fibroids (UFs).Developmental reprogramming of myometrial stem cells (MMSCs), the putative origin from which UFs originate, was investigated in vitro and in the Eker rat model by RNA-seq, ChIP-seq, RRBS, gain/loss of function analysis, and luciferase activity assays.When exposed to the endocrine-disrupting chemical (EDC) diethylstilbestrol during Eker rat development, MMSCs undergo a reprogramming of their estrogen-responsive transcriptome. The reprogrammed genes in MMSCs are known as estrogen-responsive genes (ERGs) and are activated by mixed lineage leukemia protein-1 (MLL1) and DNA hypo-methylation mechanisms. Additionally, we observed a notable elevation in the expression of ERGs in MMSCs from Eker rats exposed to natural steroids after developmental exposure to EDC, thereby augmenting estrogen activity.Our studies identify epigenetic mechanisms of MLL1/DNA hypo-methylation-mediated MMSC reprogramming. EDC exposure epigenetically targets MMSCs and leads to persistent changes in the expression of a subset of ERGs, imparting a hormonal imprint on the ERGs, resulting in a "hyper-estrogenic" phenotype, and increasing the hormone-dependent risk of UFs.© 2023. The Author(s).