STAG2 modulates environmental toxicant exposures and epigenomic heterogeneity

STAG2 调节环境毒物暴露和表观基因组异质性

• 批准号: 10594500
• 负责人: Joyce Ellen Ohm
• 金额: $ 59.72万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-20 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594500
• 关键词: 2,4,5-Trichlorophenoxyacetic acid; 2,4-Dichlorophenoxyacetic Acid; Adolescent; Affect; Aging; Aneuploidy; Animal Model; Antigens; Area; Biological Assay; Cell model; Cells; Characteristics; Chemicals; Child; Childhood; Chimeric Proteins; Complex; Connective Tissue; DNA Repair; Data; Development; Diagnosis; Diagnostic; Dioxins; Disease; Disease susceptibility; EWS-FLI1 fusion protein; Endocrine Disruptors; Environmental Exposure; Epidemiology; Epigenetic Process; Event; Evolution; Ewings sarcoma; Exposure to; Failure; Fusion Protein Expression; Gene Expression; Genetic; Genetic Transcription; Genome; Genomic Instability; Genomics; Heavy Metals; Herbicides; Heterogeneity; Incidence; Lead; Life; Limb structure; Link; Malignant Neoplasms; Measurement; Mesenchymal Stem Cells; Molecular; Mutate; Mutation; Nature; Patients; Persons; Pesticides; Play; Population; Premalignant Cell; Process; Prognosis; Regulation; Reproducibility; Research Personnel; Role; Somatic Mutation; Tetrachlorodibenzodioxin; Toxic Environmental Substances; Toxicant exposure; United States National Academy of Sciences; Vietnam; War; agent orange; biological adaptation to stress; cancer type; carcinogenicity; cohesin; cost; epigenome; epigenomics; fusion gene; loss of function mutation; member; metaplastic cell transformation; permissiveness; persistent organic pollutants; pesticide exposure; repaired; replication stress; sarcoma; toxicant; tumor; tumor heterogeneity; tumorigenesis; virtual; young adult; 2,4,5-Trichlorophenoxyacetic acid; 2,4-Dichlorophenoxyacetic Acid; Adolescent; Affect; Aging; Aneuploidy; Animal Model; Antigens; Area; Biological Assay; Cell model; Cells; Characteristics; Chemicals; Child; Childhood; Chimeric Proteins; Complex; Connective Tissue; DNA Repair; Data; Development; Diagnosis; Diagnostic; Dioxins; Disease; Disease susceptibility; EWS-FLI1 fusion protein; Endocrine Disruptors; Environmental Exposure; Epidemiology; Epigenetic Process; Event; Evolution; Ewings sarcoma; Exposure to; Failure; Fusion Protein Expression; Gene Expression; Genetic; Genetic Transcription; Genome; Genomic Instability; Genomics; Heavy Metals; Herbicides; Heterogeneity; Incidence; Lead; Life; Limb structure; Link; Malignant Neoplasms; Measurement; Mesenchymal Stem Cells; Molecular; Mutate; Mutation; Nature; Patients; Persons; Pesticides; Play; Population; Premalignant Cell; Process; Prognosis; Regulation; Reproducibility; Research Personnel; Role; Somatic Mutation; Tetrachlorodibenzodioxin; Toxic Environmental Substances; Toxicant exposure; United States National Academy of Sciences; Vietnam; War; agent orange; biological adaptation to stress; cancer type; carcinogenicity; cohesin; cost; epigenome; epigenomics; fusion gene; loss of function mutation; member; metaplastic cell transformation; permissiveness; persistent organic pollutants; pesticide exposure; repaired; replication stress; sarcoma; toxicant; tumor; tumor heterogeneity; tumorigenesis; virtual; young adult

ABSTRACT Epidemiological evidence suggests that environmental exposures during development may play a role in disease susceptibility later in life, and researchers have hypothesized that epigenetic changes induced by common toxicants such as pesticides, herbicides, endocrine disruptors, and heavy metals may be facilitating this link 1,2. The mechanisms by which these changes are induced and propagated remain challenging to dissect, largely because environmental toxicant induced changes are often 1) subtle when assayed across the bulk cell population, 2) transient in nature and therefore difficult to reproducibly detect, and/or 3) randomly distributed throughout the genome, making reproducibility and measurement of statistical significance challenging. In fact, most studies trying to link toxicant exposures directly to frank cellular transformation, including our own, have been relative failures. In virtually all cases, in order to see overt transformation, exposure studies need to be conducted in cell or animal models that already have baseline genetic or epigenetic changes that facilitate the progression to malignancy. We have exciting preliminary data that demonstrates that Ewing sarcoma cells demonstrate a significantly elevated level of transcriptional and replication stress (RS), and we propose that environmental exposures may not only induce RS and activate the RSR, but also cause epigenetic changes that precondition cells to allow for survival following expression of driver fusion proteins despite elevated levels of RS. This proposal will focus our efforts on understanding the downstream effects of TCDD exposures in mesenchymal stem cells (MSC) when paired with 2,4-D and 2,4,5-T and investigate the role of STAG2 in modulating downstream molecular events associated with environmental toxicant exposures. Our overall hypothesis is that environmental toxicant exposures cooperate with STAG2 loss to increase replication stress, ultimately leading to genomic and epigenomic instability, and creating a permissive epigenome for fusion gene expression. Three Specific Aims are proposed: SPECIFIC AIM 1: To determine whether environmental toxicant exposures increase baseline levels of replication stress in iMSC and cooperate with STAG2 loss to lead to epigenomic remodeling. SPECIFIC AIM 2: To determine whether environmental toxicant exposures cooperate with STAG2 loss to lead increased clonal genetic and epigenetic heterogeneity. SPECIFIC AIM 3: To determine whether environmental toxicant exposure leads to a permissive epigenome for survival of pre-malignant cells following fusion protein expression.

摘要流行病学证据表明，开发过程中的环境暴露可能会发挥作用 在以后的生活中的疾病易感性中的作用，研究人员假设表观遗传变化诱发了 通过常见的有毒物质，例如农药，除草剂，内分泌破坏者和重金属 促进此链接1,2。诱导这些变化并传播的机制仍然存在 具有挑战性的剖析，主要是因为环境有毒物质诱发的变化通常是1） 在整个散装细胞种群中进行测定，2）本质上的瞬态，因此难以检测到， 和/或3）随机分布在整个基因组中，使统计的可重复性和测量 重要性具有挑战性。实际上，大多数试图将毒物暴露直接与弗兰克蜂窝联系起来的研究 包括我们自己在内的转型是相对失败。在几乎所有情况下，为了查看公开 转化，暴露研究需要在已经具有基线的细胞或动物模型中进行 遗传或表观遗传学变化，促进了恶性肿瘤的发展。 我们有令人兴奋的初步数据，表明ewing肉瘤细胞表现出 转录和复制应力（RS）的水平显着升高，我们提出了环境 暴露不仅可能诱导RS并激活RSR，还会引起表观遗传变化 尽管水平升高，但在表达驱动器融合蛋白后表达驱动器融合蛋白后，细胞允许生存。这 提案将集中精力理解中充质中TCDD暴露的下游影响 干细胞（MSC）与2,4-D和2,4,5-T配对并研究Stag2在调节中的作用 与环境有毒物暴露有关的下游分子事件。我们的总体假设是 这种环境有毒物质与Stag2损失合作以增加复制应力，最终 导致基因组和表观基因组不稳定性，并为融合基因创建允许的表观基因组 表达。提出了三个具体目标： 特定目的1：确定环境有毒物的暴露是否增加了基线水平 IMSC中的复制应力并与Stag2损失合作，导致表观基因组重塑。 特定目的2：确定环境有毒物质是否会与stag2损失合作以领导 克隆遗传和表观遗传异质性增加。 特定目的3：确定环境有毒物质的暴露是否导致允许的表观基因组 融合蛋白表达后举止细胞的存活。