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.

总结 多达50%的灵长类动物基因组由转座因子（TE）组成。虽然这些元素 最初被认为是垃圾DNA，更新的技术和方法提供了对TE如何 可以促成分子和生物表型。考虑到他们现在或以前的移动能力 在宿主基因组中，TE有可能通过以下方式对生物体产生有益和有害的影响： 贡献基因调控序列。事实上，TE可以产生基因调控创新， TE是进化的新奇和适应，而TE的错误调节与包括癌症在内的各种疾病有关。 尽管TE很普遍，但我们对人体中数百万的这些元素是如何产生的知之甚少。 基因组有助于基因组功能和表达。我们的总体假设是，TE发挥其基因 在特定的环境条件下的监管效果。为了开始剖析人类TE调节，本提案将 在来自人类个体的细胞培养模型中利用进化功能基因组学方法 和我们最接近的进化亲属黑猩猩。为了支持我们的假设，我们之前的工作， 与许多其他人一样，已经表明TE确实可以通过染色质修饰，DNA 甲基化和转录因子结合。我们还表明，基因表达是动态的， 物种内部和物种之间的环境，支持非编码基因组在介导 通过基因调控的表型效应。我们利用了一种灵活的诱导多能干细胞 （iPSC）的系统来产生可以被仔细扰动的细胞类型，从而允许基因调控和 细胞反应来确定和关联。在本提案中，我们将使用iPSC技术应用于 一组人类和黑猩猩个体，连同功能基因组学和细胞分析， 转座因子在介导表型效应中的作用。首先，我们将调查TE监管 在谱系定型过程中的动态，通过询问：1）TE如何有助于灵长类动物的细胞类型特化？ 以及2）TE如何促进灵长类动物的胚层特化？第二，我们将研究 TE调节动力学响应细胞应激的问题3）应激反应如何演变， 灵长类动物？（4）TEs是否参与灵长类动物的应激反应？我们的研究将使我们了解 TE在基因组中作为调控序列的潜力，可能只在特定的细胞中显示， 或响应于扰动。这可能最终提供洞察如何异常调节，并通过 TE可以促进疾病状态。