The Role of Retroelements in Centromere Function

项目摘要 随着人类基因组通过端粒到端粒联盟的完成，一个 每个基因的着丝粒、着丝粒周围和端粒区域的完整特征 染色体，包括重复序列(卫星残留物、转座元件(TES)、逆转录病毒 插入等)是可以想象的。尽管人们普遍认为着丝粒是必不可少的 在细胞分裂过程中进行适当的染色体分离是必要的，但明显缺乏 充分了解着丝粒动力学。以前技术的局限性是核心所在 着丝粒昆虫学中的这一知识鸿沟。测序和测序的最新进展 生物信息学技术为表征和鉴定异色体提供了有效的手段 基因组的区域。以前的研究发现着丝粒区域超过了 由转录组成的更高阶卫星重复序列(Hors)的串联阵列 显示重复和逆转录的活性逆转录元件插入是必要的 为了确定拓扑相关结构域(TADS)，了解其对3D基因组的影响 结构，以及基因活性的调节。我们建议确定着丝粒如何 转座元件(CENTES)序列影响着丝粒功能，从而影响基因组 人类的正直。该项目对着丝粒景观进行了全面分析。 通过研究三个目标。第一，确定是否需要转录百分数 在着丝粒组装中的启动子，通过描绘转录位点，并测试 组装时的转录启动。第二，解释CENTs是否是表观遗传的驱动因素 通过确定着丝粒RNA转录后定位来组装着丝粒染色质， 测试转录本对着丝粒组装的影响，并描述着丝粒的移动活动。和 第三，这项研究解释了着丝粒稳定前和着丝粒后是否需要着丝粒 通过利用人类人工染色体分析和长阅读测序。这些发现将 提供了对着丝粒功能和适合性的新理解。一项全面的研究 因为这对于理解癌症等人类疾病的复杂性至关重要。这 当前的技术黄金时代使研究人员能够向旧问题提出新的问题 利用创造性的技术。

Project Summary With the completion of the Human Genome via the Telomere-to-Telomere Consortium, a complete characterization of the centromeric, pericentromeric, and telomeric regions of every chromosome, including the repeats (satellite remnants, transposable elements (TEs), retroviral insertions, etc.) is conceivable. Although it is widely accepted that centromeres are essential and necessary for proper chromosome segregation during cell division, there is a significant lack in fully understanding centromere dynamics. The limitations of previous technology are at the core of this knowledge gap in centromere entology. Current advances in sequencing and bioinformatic techniques provide an effective means to characterize and identify heterochromatic regions of the genome. Previous studies uncovered centromeric regions as more than long tandem arrays of higher order satellite repeats (HORs) that are comprised of transcriptionally active retroelement insertions displaying that repeat and retroelement transcription is necessary to identify topologically associating domains (TADs), understand the influences on 3D genome structure, and the modulation of activity of genes. We propose to determine how centromere transposable element (cenTEs) sequences influence centromeric function, and thus genome integrity in humans. This project provides a comprehensive analysis of the centromere landscape by studying three objectives. One, determine whether cenTEs are required transcription initiators in centromere assembly by delineating sites of transcription, and testing the impact of transcription initiation on assembly. Two, explain whether cenTEs are epigenetic drivers of centromere chromatin assembly by determining post-transcriptional localization of cenTE RNAs, test the impact of transcripts on centromere assembly, and describe cenTE mobile activity. And three, this study explains whether cenTEs are required for pre-and post- centromere stabilization by utilizing human artificial chromosome assays and long read sequencing. These findings will provide a novel understanding of centromere function and fitness. A comprehensive study such as this is paramount to understanding the complexities of human diseases such as cancer. This current technological golden age enables researchers to ask new questions to old problems utilizing creative techniques.