How transposable elements drive genome evolution through epigenetic mechanisms

项目总结 转座因子(TES)是一种基因组寄生虫，可以对寄主的生存能力和生育能力产生负面影响。他们 已被确定为人类遗传性疾病和癌症的原因。尽管它们有有害的影响， TES普遍存在于真核生物的基因组中，并在丰度和基因组上表现出巨大的差异 物种内部和物种之间的位置。例如，TES占据脊椎动物基因组的比例 从河豚只有6%到火蜥蜴的65%不等。超过45%的人类基因组含有TES，并且 任何两个人都至少有一千个TE插入不同。然而，目前还不清楚是什么进化 力量驱动TE变异，以及它如何影响功能，从而影响宿主的健康。大多数研究都是关于 TES的有害影响主要集中在TE对DNA的物理破坏和DNA的变化 序列。虽然这种遗传干扰有重要的后果，但这种模式忽略了 TES介导的有害表观遗传效应，包括染色质和 重组三维(3D)基因组结构。我最近的开创性研究显示，在一个 在全基因组范围内，表观遗传沉默TES可以通过顺式干扰邻近基因的功能 沉默标记的传播(TES的顺式表观遗传效应)和改变3D基因组结构(3D表观遗传 工商业污水附加费影响)。这些令人兴奋的观察结果为回答长期悬而未决的原因提供了可能性 TE含量在物种之间存在差异，以及这些差异如何影响基因组功能和 进化--我的研究计划的首要目标。我的实验室用果蝇作为主要模型 并将进化基因组学和细胞生物学相结合，以破译其功能和进化意义 TE变异的可能性。我的研究计划的一个主要目标是确定TE变异如何影响基因组 通过我新发现的TES的3D表观遗传效应进行进化。我的研究小组将使用 多层次的基因组分析(DNA、RNA、表观遗传学和3D基因组结构)以研究我们的 假设由TES介导的3D表观遗传效应可以产生不同的3D基因组组织。我们 进一步预测，这种TE介导的3D基因组结构变异可以通过以下方式塑造基因组进化 影响基本的遗传过程。此外，我的实验室试图识别分子和 物种间TE含量差异的进化机制。我们将用果蝇 遗传学和转基因，以确定宿主遗传因素，调节TES的表观遗传效应在顺式和 在3D核空间。此外，我们将把比较进化基因组学和实验相结合 进化来研究我们的假设，即这些寄主遗传因素的物种间差异对 TES的不同表观遗传效应，并最终推动不同内容的演变 果蝇物种。我们的发现将为理解真核生物基因组进化提供新的基础 并为TES在人类健康和疾病中的作用开辟了新的视角。

PROJECT SUMMARY Transposable elements (TEs) are genomic parasites that can negatively impact host viability and fertility. They have been identified as the causes of inherited human disorders and cancers. Despite their detrimental effects, TEs are prevalent across eukaryotic genomes and exhibit dramatic variation in abundance and genomic positions within and between species. For instance, the proportion of vertebrate genomes occupied by TEs ranges from only 6% in pufferfish to 65% in salamander. Over 45% of the human genome harbors TEs, and any two people differ by at least a thousand TE insertions. However, it remains unclear what evolutionary forces drive TE variation and how that influences functions and, thereby, host health. Most studies of the harmful effects of TEs have centered on TE-mediated physical disruption of DNA and changes in DNA sequences. While such genetic disturbances have important consequences, this paradigm overlooks the detrimental epigenetic effects mediated by TEs, including biochemical modifications of chromatin and reorganization of three-dimensional (3D) genome structures. My recent pioneering studies revealed, on a genome-wide scale, that epigenetically silenced TEs can perturb the function of neighboring genes through cis spreading of silencing marks (cis epigenetic effects of TEs) and alter 3D genome organization (3D epigenetic effects of TEs). These exciting observations offer a possibility to answer long-unresolved questions about why there are between-species differences in TE content and how these differences affect genome function and evolution—the overarching goals of my research program. My laboratory uses Drosophila as a primary model and integrates evolutionary genomics and cell biology to decipher the functional and evolutionary significance of TE variation. One major goal of my research program is to determine how TE variation influences genome evolution through my newly discovered 3D epigenetic effects of TEs. My research group will use integrative genomic analysis at multiple levels (DNA, RNA, epigenetics, and 3D genome structures) to investigate our hypothesis that the 3D epigenetic effects mediated by TEs can produce varying 3D genome organization. We further predict that this TE-mediated variation in 3D genome structures can shape genome evolution by affecting fundamental genetic processes. In addition, my laboratory seeks to identify the molecular and evolutionary mechanisms contributing to between-species differences in TE content. We will use Drosophila genetics and transgenics to identify host genetic factors that modulate the epigenetic effects of TEs in cis and in 3D nuclear space. Furthermore, we will combine comparative evolutionary genomics and experimental evolution to investigate our hypothesis that between-species variation in these host genetic factors contributes to varying epigenetic effects of TEs and ultimately drives the evolution of divergent TE content across Drosophila species. Our discoveries will provide a novel basis for understanding eukaryotic genome evolution and open new perspectives for TEs' roles in human health and disease.