Epigenomics of Bisphenol A Exposure and Disease Risk

双酚 A 暴露和疾病风险的表观基因组学

• 批准号: 8539617
• 负责人: Tim H.-M. Huang
• 金额: $ 32.98万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8539617
• 关键词: Adult; Affect; Animals; Base Sequence; Beverages; Biological Assay; Biological Markers; Breast; Cancer Patient; Cells; Chemicals; Chromatin; Collagen; Complex; CpG Islands; Cultured Cells; Cytology; Cytoplasm; DNA Methylation; DNA Methyltransferase; DNA Modification Methylases; DNA Structure; Dependency; Development; Diethylstilbestrol; Dimethyl Sulfoxide; Dose; Environmental Estrogen; Epidemiologic Studies; Epidemiology; Epigenetic Process; Epithelial; Epithelial Cells; Epoxy Resins; Estradiol; Estrogen Nuclear Receptor; Estrogen Receptor 1; Estrogen Receptors; Estrogens; Exposure to; Food; Gene Expression; Genes; Genome; Health; Histones; Homeostasis; Human; Human Genome; Immunofluorescence Immunologic; In Vitro; Individual; Injury; Ligands; Longevity; Mammary Neoplasms; Mammary gland; Maps; Memory; Modeling; Molecular; Monitor; Myoepithelial cell; Neoplastic Cell Transformation; Nuclear; Nucleic Acid Regulatory Sequences; Organ; Pattern; Perinatal Exposure; Physiological; Plasticizers; Polycomb; Process; Production; Proliferating; Protocols documentation; Puberty; Recording of previous events; Risk; Risk Assessment; Rodent; Signal Transduction; Stem cells; Suspension Culture; System; Temperature; Tissues; Transcription Repressor/Corepressor; X Inactivation; bisphenol A; crosslink; daidzein; disorder risk; environmental agent; epigenetic marker; epigenomics; exposed human population; histone modification; imprint; malignant breast neoplasm; mammary gland development; nonylphenol; planetary Atmosphere; polycarbonate plastic; polymerization; prenatal; progenitor; programs; promoter; response; self-renewal; sensor; transcription factor; xenoestrogen

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.

描述(由申请人提供)：我们建议研究正常乳腺上皮细胞对生理刺激和环境扰动的表观遗传学变化。综合组学方法将被用来确定受配体刺激的雌激素受体(ER)1阳性细胞的整体染色质分布。ER1信号的复杂调控网络被激活，伴随着反应基因中染色质的变化。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，当信号被下一周期的配体激活时，准备接受转录因子或抑制物。当上皮祖细胞持续暴露在雌激素增塑剂如双酚A(BPA)中时，染色质动态的动态平衡被扰乱。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。抑制性组蛋白标记、多梳抑制物和DNA甲基转移酶的逐步获得可能发生在这些基因中。这种损伤信息可以遗传地传递给分化的后代，DNA甲基化逐渐积累在目标CpG岛上。这些CpG岛的表观基因组图谱可能识别潜在的生物标记物，这些生物标记物被用作环境传感器，用于监测人类对环境雌激素的暴露。

项目成果

Hierarchical modularity in ERα transcriptional network is associated with distinct functions and implicates clinical outcomes.

• DOI: 10.1038/srep00875
• 发表时间: 2012
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Tang, Binhua;Hsu, Hang-Kai;Hsu, Pei-Yin;Bonneville, Russell;Chen, Su-Shing;Huang, Tim H-M.;Jin, Victor X.
• 通讯作者: Jin, Victor X.

Methods in DNA methylation profiling.

• DOI: 10.2217/epi.09.31
• 发表时间: 2009-12
• 期刊: Epigenomics
• 影响因子: 3.8
• 作者: Zuo T;Tycko B;Liu TM;Lin JJ;Huang TH
• 通讯作者: Huang TH