Form and function of our Janus faced genome

项目名称：我们的Janus面临的基因组的形式和功能 通过逆转录将RNA转化为DNA， 人类基因组：RNA衍生的DNA拷贝的插入使人类基因组的质量大约增加了一倍。 我们的遗传物质然而，逆转录RNA的整合是一个重要的因素。 即使对于最成功的基因组寄生虫（例如逆转录病毒， 反转录转座子和假基因）。逆转录的复制品不能 一体化可以被认为是罗马神雅努斯的缩影：有一张脸，他们 凝视过去作为一个不完美的复制以前的生活（即RNA，他们是 他们以另一张面孔，展望未来，能够指挥 它们的分子环境的命运。值得注意的是，这些的身份和功能 基因组的错配，在很大程度上是在传统的DNA景观范围之外， 未经探索，但预计将是巨大而强大的。 我们发现内源性cDNA形成（即逆转录的DNA衍生的 来自宿主RNA）是稳健的并且具有重要的生物学和疾病修饰功能。 阻断逆转录可以阻止内源性cDNA的形成，有趣的是， 还阻断内源性cDNA介导的小鼠失明模型。在这里，我们将 扩展这些观察，系统地分析宿主衍生的反向 转录组产生的第一个草案图谱的身份和功能的内源性 cDNA，在健康和疾病中。我们还将通过实验证明 内源性cDNA的分子和代谢途径，并提供了一个替代 核苷类逆转录酶抑制剂的毒性解释（例如， 周围神经病变和发育缺陷）。我们希望我们的工作能证明 宿主RNA的碰撞和遗传信息的双向流动 产生了一种强大的调节分子， 健康和疾病，并可以利用来理解和操纵的基本原则， 细胞生物学

Project title: Form and function of our Janus faced genome The conversion of RNA into DNA via reverse transcription has transformed the human genome: insertion of RNA-derived DNA copies has roughly doubled the mass of our hereditary material. However, integration of reverse transcribed RNAs is an inefficient process, even for the most successful genomic parasites (e.g. retroviruses, retrotransposons, and pseudogenes). The reverse transcribed copies that fail to integrate may be considered microcosms of the Roman god Janus: with one face, they gaze towards the past as an imperfect copy of a previous life (i.e. the RNA they are derived from), and with another face, they look towards the future, capable of directing the fate of their molecular environment. Remarkably, the identity and function of these genomic misfits that lie outside the confines of the traditional landscape of DNA is largely unexplored, but expected to be vast and powerful. We find that endogenous cDNA formation (i.e. reverse transcribed DNA derived from host RNA) is robust and has important biological and disease-modifying function. Blocking reverse transcription prevents endogenous cDNA formation, and interestingly, also blocks an endogenous cDNA-mediated mouse model of blindness. Here, we will extend these observations to systematically analyze the host-derived reverse transcriptome to produce the first draft atlas of the identity and function of endogenous cDNA, in health and disease. We will also experimentally demonstrate the relevance of endogenous cDNA to molecular and metabolic pathways, and provide an alternate explanation of toxicity attributed nucleoside reverse transcriptase inhibitors (e.g. peripheral neuropathy and developmental defects). We expect our work to demonstrate that the collision of host-derived RNA and the bidirectional flow of genetic information produces a powerful regulatory class of hereto underappreciated molecules that control health and disease, and can be harnessed to understand and manipulate basic tenets of cellular biology.