Epigenomics of Bisphenol A Exposure and Disease Risk

描述（由申请人提供）：我们建议研究正常乳腺上皮细胞响应生理刺激和环境扰动的表观遗传变化。综合组学方法将用于确定配体刺激的雌激素受体 (ER)1 阳性细胞的整体染色质谱。 ER1 信号传导的复杂调控网络随着响应基因中染色质的改变而被激活。然后这些基因的表达恢复到基础水平。染色质处于半开放状态，当信号被下一个配体周期激活时，准备接收转录因子或阻遏物。当上皮祖细胞持续暴露于双酚 A (BPA) 等雌激素增塑剂时，染色质动态的稳态就会受到干扰。我们假设响应基因的一个子集被重新编程以经历永久沉默。这些基因中可能会逐步获得抑制性组蛋白标记、多梳抑制子和 DNA 甲基转移酶。这种损伤信息可以遗传地传递给分化的后代，并且 DNA 甲基化在目标 CpG 岛中逐渐积累。这些 CpG 岛的表观基因组图谱可以识别潜在的生物标志物，这些生物标志物可用作环境传感器来监测人类暴露于环境雌激素的情况。

DESCRIPTION (provided by applicant): We propose to study epigenetic changes in normal breast epithelial cells responding to physiological stimulation and environmentally perturbation. Integrative omic approaches will be used to determine global chromatin profiles in estrogen receptor (ER)1-positive cells stimulated with ligands. Complex regulatory networks of ER1 signaling are activated with concomitant alterations of chromatin in responsive genes. The expression of these genes then returns to the basal level. Chromatin is in a semi-open state, poised to receive transcription factors or repressors when signaling is activated by the next cycle of ligand. The homeostasis of chromatin dynamics is perturbed when epithelial progenitor cells are continually exposed to estrogenic plasticizers like bisphenol A (BPA). We hypothesize that a subset of responsive genes is reprogrammed to undergo permanent silencing. Step-wise acquisition of repressive histone marks, polycomb repressors, and DNA methyltransferases may take place in these genes. This injury information can be heritably transmitted to the differentiated progeny, and DNA methylation is progressively accumulated in target CpG islands. Epigenomic mapping of these CpG islands may identify potential biomarkers that are used as environmental sensors for monitoring human exposures to environmental estrogens.