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

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.

流行病学证据表明，发育过程中的环境暴露可能对发育过程中的免疫功能起重要作用。 在以后的生活中疾病易感性中的作用，研究人员假设表观遗传变化诱导 常见的有毒物质，如杀虫剂，除草剂，内分泌干扰物和重金属， 促进该链接1、2。引起和传播这些变化的机制仍然存在 解剖具有挑战性，主要是因为环境毒物引起的变化往往是微妙的， 在整个细胞群中测定，2）本质上是瞬时的，因此难以重复检测， 和/或3）随机分布在整个基因组中，使得可再现性和统计测量 意义挑战。事实上，大多数试图将有毒物质暴露与弗兰克细胞 包括我们自己在内的转型都是相对失败的。在几乎所有的情况下，为了看到明显的 转化，暴露研究需要在已经有基线的细胞或动物模型中进行。 促进恶性进展的遗传或表观遗传变化。 我们有令人兴奋的初步数据表明尤文肉瘤细胞表现出 转录和复制应激（RS）水平显着升高，我们提出，环境 暴露不仅可以诱导RS和激活RSR，还可以引起表观遗传变化， 细胞以允许在表达驱动融合蛋白后存活，尽管RS水平升高。这 这项提案将集中我们的努力，了解TCDD暴露在间充质细胞的下游影响， 当与2，4-D和2，4，5-T配对时，研究STAG 2在调节细胞增殖中的作用。 与环境毒物暴露相关的下游分子事件。我们的总体假设是 环境毒物暴露与STAG 2缺失共同作用，最终增加复制压力， 导致基因组和表观基因组的不稳定性，并产生融合基因的容许表观基因组 表情提出了三个具体目标： 具体目标1：确定环境毒物暴露是否会增加 iMSC中的复制应激并与STAG 2缺失协同导致表观基因组重塑。 具体目标2：确定环境毒物暴露是否与STAG 2铅损失相关 增加克隆遗传和表观遗传异质性。 具体目标3：确定环境毒物暴露是否会导致一个允许的表观基因组， 融合蛋白表达后癌前细胞的存活。