Developmental reprogramming of myometrial stem cells by endocrine disruptor linking to risk of uterine fibroids.
Developmental reprogramming of myometrial stem cells by endocrine disruptor linking to risk of uterine fibroids.
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DOI：
10.1007/s00018-023-04919-0
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发表时间：
2023-08-31
影响因子：
8
通讯作者：
Al-Hendy, Ayman
中科院分区：
文献类型：
--
作者：
Yang, Qiwei;Ali, Mohamed;Trevino, Lindsey S.;Mas, Aymara;Al-Hendy, Ayman
关键词：
组织和器官生长的阶段非常容易受到环境影响，但目前尚不清楚在此期间暴露如何导致表观基因组的变化并增加子宫肌瘤（UF）等子宫肌瘤相关疾病的风险。通过RNA-seq、ChIP-seq、RRBS、功能获得/丧失分析和荧光素酶活性测定，在体外和Eker大鼠模型中研究了子宫肌层干细胞（MMSC）（UF的假定起源）的发育重编程。在Eker大鼠发育过程中，当暴露于内分泌干扰化学品（EDC）己烯雌酚时，MMSC会对其雌激素反应性转录组进行重编程。MMSC中的重编程基因被称为雌激素应答基因（ERG），并通过混合谱系白血病蛋白-1（MLL 1）和DNA低甲基化机制激活。此外，我们观察到一个显着的Eker大鼠暴露于天然类固醇后，发育暴露于EDC，从而增强雌激素活性的MMSCs中的ERG的表达升高。我们的研究确定了MLL 1/DNA低甲基化介导的MMSC重编程的表观遗传机制。EDC暴露在表观遗传学上靶向MMSC，并导致ERG亚组表达的持续变化，在ERG上产生激素印记，导致“高雌激素”表型，并增加UF的雌激素依赖性风险。在线版本包含补充材料，可通过10.1007/s 00018 -023-04919-0获得。
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. The online version contains supplementary material available at 10.1007/s00018-023-04919-0.
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DOI：
10.1158/1541-7786.mcr-11-0605
发表时间：
2012-04
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Greathouse KL;Bredfeldt T;Everitt JI;Lin K;Berry T;Kannan K;Mittelstadt ML;Ho SM;Walker CL
通讯作者：
Walker CL
影响因子：
3.7
作者：
Cheong A;Zhang X;Cheung YY;Tang WY;Chen J;Ye SH;Medvedovic M;Leung YK;Prins GS;Ho SM
通讯作者：
Ho SM
影响因子：
4.7
作者：
Caldon CE
通讯作者：
Caldon CE
影响因子：
10.5
作者：
Herbert, Katharine;Binet, Romuald;Goding, Colin R.
通讯作者：
Goding, Colin R.
影响因子：
10.4
作者：
D'Aloisio, Aimee A.;Baird, Donna D.;Sandler, Dale P.
通讯作者：
Sandler, Dale P.