Environmental Epigenomics and Precision Environmental Health

环境表观基因组学和精准环境健康

• 批准号: 10623309
• 负责人: Dana Dolinoy
• 金额: $ 87.45万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-11 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623309
• 关键词: Advanced Development; Affect; Animal Model; Animals; Azacitidine; Belief; Biological Availability; Birth; Blood; Brain; Cells; Chromatin Structure; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; DNA Methylation; Disease; Disease susceptibility; Endocrine; Endocrine Disruptors; Environment; Environmental Health; Epidemiology; Epigenetic Process; Exposure to; Gene Expression; Genes; Goals; Health; Heritability; Human; Human Cell Line; In Vitro; Lead; Life; Malignant Neoplasms; Metals; Mitotic; Modification; Mus; Mutate; Outcome; Perinatal Exposure; Physiological; RNA; Research; Research Support; Resources; Risk; Rodent; Sampling; Somatic Cell; System; Technology; Therapeutic; Tissues; Toxicant exposure; Toxicology; Training; Untranslated RNA; Vision; cell type; cohort; disorder risk; epigenome; epigenome editing; epigenomics; experimental study; flexibility; human tissue; imprint; in vivo; innovation; mouse model; phthalates; piRNA; sex; tool; toxicant; transcription activator-like effector nucleases

Abstract Toxicant exposures early in life adversely affect health outcomes in both animal models and humans, in part due to epigenetic mechanisms. Accumulating studies also indicate that exposures' impact on the epigenome can be tissue and even cell specific. Yet, toxicoepigenetic animal studies are often conducted with single tissues in bulk and/or limited epigenomic targets (e.g. DNA methylation). Additionally, epigenetic epidemiology analysis of toxicants is almost always restricted to biologically available, “surrogate” (e.g. blood) samples. Using a combination of toxicological and epidemiological approaches, the first of two overarching goals of this Revolutionizing Innovative, Visionary Environmental Health Research (RIVER) application is to advance the understanding of the effects of representative perinatal exposures (e.g. metals including lead and endocrine active compounds including phthalates) on the epigenome and longitudinal health risks. To accomplish this, we will use human physiologically relevant mouse models and longitudinal human birth cohort samples alongside targeted and unbiased approaches to evaluate DNA methylation, non-coding RNA, chromatin structure, and gene expression in both sexes in multiple tissues, incorporating single cell approaches when relevant. Ultimately, we seek to identify tissue-specific epigenomic signatures of exposures contributing to disease susceptibility as well as regions of the epigenome that may be interrogated with the use of surrogate tissues. While precision modification of the epigenome holds great promise to modify environmentally induced changes and reduce disease risk, it is currently out of reach using common available global (e.g. azacytidine) and targeted (e.g. TALENs, CRISPR) systems. Thus, our second overarching goal is to advance the development of a suite of tools, based on the PIWI-interacting RNA (piRNA) system to transform precision environmental health, while avoiding drawbacks of current technology. In mice, we have shown that piRNA and associated processing machinery are present and active in somatic tissues, especially the brain, in contrast to prior belief that the piRNA suppression system was restricted to the germ-line. Evidence from our viable yellow agouti (Avy) mouse experiments supports piRNA-based DNA methylation induction in vivo. Thus, we propose to use this class of RNA to develop precision environmental health tools to target specific genes and loci for stable, mitotically heritable, silencing in somatic cells. First, we will evaluate piRNA/PIWIL machinery across somatic human tissues to prioritize cell types with high endogenous piRNA machinery for epigenetic editing. Then, we will develop synthetic piRNAs to target DNA methylation in vitro in exposed rodent and human cell lines. The research will expand the repertoire of human epigenome editing tools resulting in therapeutics to treat a broad array of environmental and epigenetic diseases including imprinted gene disorders and cancer. The vision for the flexible and sustained RIVER support is to innovate the field of environmental epigenomics, develop translational tools for precision epigenome editing, and be a resource for research and training.

摘要 在动物模型和人类中，生命早期的有毒物质暴露对健康结果产生不利影响，部分原因是 是由于表观遗传机制。越来越多的研究还表明，暴露对表观基因组的影响 可以是组织甚至细胞特异性的。然而，毒理表观遗传动物研究通常是用单一的 大量组织和/或有限的表观基因组靶标（例如DNA甲基化）。此外，表观遗传流行病学 毒物的分析几乎总是限于生物学上可获得的“替代”（例如血液）样品。 使用毒理学和流行病学方法的组合，本研究的两个总体目标中的第一个 革命性的创新，有远见的环境健康研究（河流）的应用是推进 了解围产期典型接触的影响（例如，包括铅和内分泌在内的金属 活性化合物，包括邻苯二甲酸酯）对表观基因组和纵向健康风险的影响。为了做到这一点，我们 将使用人类生理学相关的小鼠模型和纵向人类出生队列样本， 有针对性和公正的方法来评估DNA甲基化，非编码RNA，染色质结构， 在多种组织中两性的基因表达，相关时结合单细胞方法。 最终，我们寻求确定导致疾病的暴露的组织特异性表观基因组特征 易感性以及可以使用替代组织进行询问的表观基因组区域。 虽然表观基因组的精确修饰在改变环境诱导的变化方面有很大的希望， 和降低疾病风险，目前使用常见的全球（如氮杂胞苷）和 靶向（例如TALEN、CRISPR）系统。因此，我们的第二个总体目标是推动发展 一套工具，基于PIWI相互作用RNA（皮尔纳）系统， 健康，同时避免现有技术的缺点。在小鼠中，我们已经证明皮尔纳和相关的 与先前的看法相反，加工机制存在于躯体组织中，特别是大脑中，并且是活跃的。 皮尔纳抑制系统仅限于生殖系。从我们的黄色琼脂中 (Avy)小鼠实验支持体内基于piRNA的DNA甲基化诱导。因此，我们建议使用 这类RNA开发精确的环境健康工具，以靶向特定的基因和位点， 有丝分裂遗传，体细胞沉默。首先，我们将评估跨体细胞的皮尔纳/PIWIL机制。 人类组织优先考虑具有高内源性皮尔纳机制的细胞类型用于表观遗传编辑。然后我们 将开发合成的piRNA，在暴露的啮齿动物和人类细胞系中体外靶向DNA甲基化。的 研究将扩大人类表观基因组编辑工具的库，从而产生治疗广泛的 一系列环境和表观遗传疾病，包括印记基因紊乱和癌症。的愿景 灵活和持续的RIVER支持是创新环境表观基因组学领域， 翻译工具的精确表观基因组编辑，并成为研究和培训的资源。