Epigenetic mechanisms in Transgenerational Effects of an Environmental Pollutant

环境污染物跨代效应的表观遗传机制

基本信息

批准号：
10658858
负责人：
Mitzi Nagarkatti
金额：
$ 48.12万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-24 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658858
关键词：
ATAC-seq Adult Affect Anti-Inflammatory Agents Antigens Aryl Hydrocarbon Receptor Azacitidine Bacterial Infections Biological Assay Biosensor CD4 Positive T Lymphocytes Cell Differentiation Induction Cell Differentiation process Cells Cessation of life Chromatin Complex DNA DNA Methylation DNA Modification Methylases Data Developing Countries Development Dioxins Down-Regulation Endocrine Disruptors Environmental Pollutants Environmental Risk Factor Enzymes Epigenetic Process Exposure to FOXP3 gene Female Fertilization GATA3 gene Gene Expression Generations Genes Genomic Imprinting Genomics Histones IL17 gene Immune response Infection Inflammation Inflammatory Interferon Type II Interleukin-10 Interleukin-4 Life Ligands Maternal Exposure Mediating Methylation Methyltransferase MicroRNAs Modality Modeling Morbidity - disease rate Mothers Mus Neonatal Newborn Infant Parents Partner in relationship Paternal Exposure Pathway interactions Peripheral Phase Phenotype Play Pregnancy Preventive Receptor Activation Regulatory T-Lymphocyte Resistance Role S-Adenosylhomocysteine S-Adenosylmethionine Site Staphylococcal Enterotoxin B Staphylococcal Infections Staphylococcus aureus Superantigens System T cell clonality T cell differentiation T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte T-cell diversity T-cell receptor repertoire Testing Tetrachlorodibenzodioxin Th1 Cells Therapeutic Time Toxic Shock Syndrome Toxic effect Transfection Transforming Growth Factor beta Up-Regulation aryl hydrocarbon receptor ligand chromatin remodeling complementarity-determining region 3 cytokine cytokine release syndrome demethylation differential expression endocrine disruptor exposure epigenome genome-wide histone methylation histone modification immunoregulation immunotoxicity imprint inhibitor innovation insight male mortality novel overexpression permissiveness polarized cell pregnant promoter reproductive restriction enzyme transcription factor transmission process

项目摘要

Abstract Bacterial infections during neonatal phase cause high rates of morbidity and mortality, and in developing countries are responsible for 26% of deaths. Environmental factors present during pregnancy are known to impact life-threatening infections in newborns, including Staph. aureus infections, although the mechanisms are unclear. Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental pollutant, which acts through the cytosolic aryl hydrocarbon receptor (AhR). While AhR has been well characterized for its role in regulating toxicity mediated by TCDD, recently, AhR activation was shown to regulate T cell differentiation into T regs or Th17 cells. We have generated exciting preliminary data indicating that AhR activation by TCDD suppresses T cell response to Staphylococcal enterotoxin B (SEB) and that this is mediated by epigenetic pathways including dysregulation in microRNA (miR) expression, DNA methylation, and histone modifications in activated T cells. More importantly, our studies have suggested that TCDD may exert transgenerational epigenetic effects on T cells. Based on the importance of Staph infections discussed above, we will use SEB as an antigen to test the central hypothesis that AhR activation of Vβ8+ T cells by TCDD, plays a crucial role in reducing pro-inflammatory Th1/Th17 cells as well as increasing anti-inflammatory Tregs and its subsets by modulating miR expression, and that this may depend on DNA methylation, histone modifications and chromatin remodeling that could be transmitted transgenerationally. Inasmuch as, SEB can activate Vβ8+ T cells which constitute ~30% of peripheral T cells, our studies are aimed at determining whether TCDD-induced changes persist in F0, F1, F2, and F3 generations following maternal exposure during pregnancy to TCDD or maternal/paternal exposure prior to mating (F0). In Aim 1, we will determine the transgenerational effects of TCDD on SEB-induced CD4+ T cell differentiation. We will test the effect of TCDD on the TCR clonality and diversity of the Vβ8+ CD4+ T cell response (Th1, 2, 17, Tregs) to SEB. In Aim 2, we will study the role of specific miRs in CD4+ T cell differentiation in F0-F3 generations. Furthermore, transfection of T cells with specific miR mimics or antagomirs will be performed to reverse T cell differentiation induced by TCDD and determine whether the effects persist across generations. In Aim 3, we will determine the role of genome-wide and locus-specific DNA methylation on CpG sites on promoters of specific miR that regulate differential expression of Th/Treg response to SEB across the generations. Aim 4 will elucidate the permissive and repressive histone modification and chromatin accessibility in TCDD-mediated transgenerational dysregulation of miR involved in CD4+ T cell differentiation. Lastly, whether these changes are imprinted through male or female germline will be assessed. The proposed studies are highly significant in that novel epigenetic pathways of TCDD-mediated immunotoxicity across generations will be identified. Also, understanding how AhR ligands mediate differential effects through epigenetic pathways would lead to development of innovative preventive and therapeutic modalities.

抽象的新生儿阶段的细菌感染导致高发病率和死亡率，并且在发育中已知 26% 的妊娠期死亡是由环境因素造成的。影响新生儿的危及生命的感染，包括金黄色葡萄球菌感染，尽管其机制是。目前尚不清楚，四氯二苯并二恶英 (TCDD) 是一种环境污染物，通过细胞质发挥作用。芳烃受体（AhR），而 AhR 因其在调节毒性方面的作用而得到了很好的表征。在 TCDD 介导下，最近，AhR 激活被证明可以调节 T 细胞分化为 T reg 或 Th17 我们已经生成了令人兴奋的初步数据，表明 TCDD 激活 AhR 会抑制 T 细胞。对葡萄球菌肠毒素 B (SEB) 的反应，这是由表观遗传途径介导的，包括激活 T 细胞中 microRNA (miR) 表达、DNA 甲基化和组蛋白修饰的失调。更重要的是，我们的研究表明TCDD可能对T产生跨代表观遗传效应。基于上面讨论的葡萄球菌感染的重要性，我们将使用 SEB 作为抗原来检验中心假设，AhR 通过 TCDD 激活 Vβ8+ T 细胞，在减少促炎性 Th1/Th17 细胞以及增加抗炎性 Tregs 及其亚群调节 miR 表达，这可能取决于 DNA 甲基化、组蛋白修饰和染色质重塑可以跨代传递，因为 SEB 可以激活 Vβ8+。 T 细胞约占外周 T 细胞的 30%，我们的研究旨在确定 TCDD 是否诱导母亲在怀孕期间接触 TCDD 后，F0、F1、F2 和 F3 代的变化持续存在在目标 1 中，我们将确定交配前母体/父体暴露的情况（F0）。 TCDD 对 SEB 诱导的 CD4+ T 细胞分化的影响我们将测试 TCDD 对 TCR 克隆和分化的影响。 Vβ8+ CD4+ T 细胞（Th1、2、17、Tregs）对 SEB 反应的多样性在目标 2 中，我们将研究特定的作用。 F0-F3代CD4+ T细胞分化中的miRs 此外，用特异性miR转染T细胞。将进行模拟或antagomir来逆转TCDD诱导的T细胞分化，并确定是否在目标 3 中，我们将确定全基因组和位点特异性的作用。调节 Th/Treg 差异表达的特定 miR 启动子上 CpG 位点的 DNA 甲基化目标 4 将阐明各代人对 SEB 的反应。 TCDD 介导的 CD4+ T 细胞 miR 跨代失调中的染色质可及性最后，将评估这些变化是否通过男性或女性种系印记。拟议的研究对于 TCDD 介导的免疫毒性的新表观遗传途径非常重要此外，还将了解 AhR 配体如何通过介导差异效应。表观遗传途径将导致创新预防和治疗方式的发展。