Dynamic regulatory impact of human transposable elements on gene expression

人类转座元件对基因表达的动态调控影响

• 批准号: 10712515
• 负责人: Michelle Claire Ward
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-04 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712515
• 关键词: Binding; Cardiovascular Diseases; Cell Culture Techniques; Cells; Cellular Assay; Cellular Stress; Complex; DNA Methylation; DNA Transposable Elements; Disease; Elements; Environment; Evolution; Gene Expression; Gene Expression Regulation; Genome; Genomic approach; Genomics; Germ Layers; Human; Human Genome; Individual; Junk DNA; Malignant Neoplasms; Mediating; Modeling; Molecular; Organism; Pan Genus; Phenotype; Prevalence; Primates; Regulation; Regulator Genes; Regulatory Element; Research; Role; Specific qualifier value; Stress; System; Tissues; Untranslated RNA; Work; biological adaptation to stress; cell type; chromatin modification; flexibility; functional genomics; induced pluripotent stem cell; induced pluripotent stem cell technology; innovation; insight; new technology; novel strategies; response; transcription factor

SUMMARY As much as 50% of primate genomes are comprised of transposable elements (TEs). While these elements were originally thought to be junk DNA, newer technologies and approaches have provided insight into how TEs can contribute to molecular and organismal phenotypes. Given their current or previous ability to move within host genomes, TEs have the potential to exert both beneficial and deleterious effects on the organism by contributing gene regulatory sequence. Indeed, TEs can generate gene regulatory innovation leading to evolutionary novelty and adaptation, while TE mis-regulation associates with various diseases including cancer. Despite the prevalence of TEs we understand relatively little about how millions of these elements in the human genome contribute to genome function and expression. Our overarching hypothesis is that TEs exert their gene regulatory effects in specific environmental contexts. To begin to dissect human TE regulation, this proposal will make use of evolutionary functional genomics approaches in a cell culture model derived from human individuals and our closest evolutionary relatives the chimpanzee. In support of our hypothesis, our previous work, together with that of many others, has indicated that TEs can indeed be regulated through chromatin modifications, DNA methylation and transcription factor binding. We have also shown that gene expression is dynamic in response to the environment within and between species, which supports the role of the non-coding genome in mediating phenotypic effects through gene regulation. We have taken advantage of a flexible induced pluripotent stem cell (iPSC) based system to generate cell types that can be carefully perturbed, allowing for gene regulatory and cellular responses to be determined and correlated. In this proposal we will use iPSC technology applied to a panel of human and chimpanzee individuals, together with functional genomics and cellular assays to dissect the role of transposable elements in mediating phenotypic effects. First, we will investigate TE regulatory dynamics during lineage commitment by asking: 1) How do TEs contribute to cell type specification in primates? and 2) How do TEs contribute to germ layer specification in primates? Second, we will investigate the evolution of TE regulatory dynamics in response to cellular stress by asking 3) How do stress responses evolve in primates? and 4) Do TEs contribute to stress responses in primates? Our research will result in an understanding of the potential for TEs to act as regulatory sequence in the genome that may only be revealed in particular cell states, or in response to perturbation. This may ultimately provide insight into how aberrant regulation of, and by TEs can contribute to disease states.

概括 多达50％的灵长类动物基因组由转座元素（TES）组成。而这些元素 最初被认为是垃圾DNA，较新的技术和方法为TES提供了深入的了解 可以有助于分子和有机表型。考虑到他们当前或以前的移动能力 宿主基因组，TE有可能对生物体发挥有益和有害影响 促进基因调节序列。确实，TE可以产生基因调节创新，导致 进化的新颖性和适应性，而不良调节与包括癌症在内的各种疾病相关。 尽管TE的普遍存在，我们对人类中的数百万元素的了解相对较少 基因组有助于基因组功能和表达。我们的总体假设是施加其基因 在特定环境环境中的监管效果。为了开始剖析人类的监管，该提议将 利用从人个体得出的细胞培养模型中的进化功能基因组学方法 以及我们最亲密的进化亲戚黑猩猩。支持我们的假设，我们以前的工作 与其他许多其他相关联的情况下，TES确实可以通过染色质修饰，DNA来调节 甲基化和转录因子结合。我们还表明，基因表达在响应中是动态的 到物种内部和物种之间的环境，这支持非编码基因组在介导中的作用 通过基因调控表型效应。我们已经利用了灵活的诱导多能干细胞 （IPSC）基于可以仔细干扰的细胞类型的系统，从而允许基因调节和 细胞反应要确定和相关。在此提案中，我们将使用应用于A的IPSC技术 人和黑猩猩个体的小组，以及功能性基因组学和细胞测定法 可转座元素在介导表型效应中的作用。首先，我们将调查调节性 通过问：1）TES如何促进灵长类动物的细胞类型规范？ 2）TE如何促进灵长类动物的细菌层规范？其次，我们将调查进化 通过询问3）应力反应如何演变 灵长类动物？ 4）TE是否有助于灵长类动物的压力反应？我们的研究将导致理解 TE充当基因组调节序列的潜力，而这种序列只能在特定细胞中揭示 状态或响应扰动。这最终可能提供了有关如何和通过的异常监管以及 TE可以促进疾病状态。