Protection of early embryogenesis and pluripotent stem cells against genetic parasites through a primitive immune system

项目总结 移动DNA的遗迹让我们的基因组看起来像是暴徒场景的后遗症。更糟糕的是，一些内源性的 反转录转座子并没有消失，而是在个体发育的早期仍然聚集在我们的细胞中。他们的行为会严重影响到 破坏新生胚胎的基因组，并导致零星疾病和不孕。最近，我们发现 一种机制，通过这种机制，相邻的细胞主动移除未能经历沉默的多能细胞 内源性反转录转座子。我们的假设是，存在一种有条件的警务机制，这让人想起 原始免疫系统。我们认为，多能干细胞感知其内源性逆转录病毒载量 相邻的细胞，如果它高于它们自己的细胞，则采取行动杀死并移除过载的细胞。完工后 在概述的工作中，我们将(I)探索以前未曾探索过的涉及细胞的感知机制 相互“嗅探”内源性逆转录病毒和移除未能使其基因沉默的细胞 寄生虫(目标1和目标2)和(2)测试该系统是否可调节和受免疫调节(目标1和目标2) 3)。这些结果将产生积极影响，因为它们将迫使我们将注意力从单纯的 细胞内在防御策略，以考虑一个更加微妙的系统，在这个系统中，细胞不断地 相互监测内源性逆转座子相关的健康状况。我们的调查范围将提供新的 针对妊娠丢失和不孕症的基因诊断和干预目标。

PROJECT SUMMARY Relics of mobile DNA make our genomes look like the aftermath of a mob scene. Even worse, some endogenous retrotransposons did not die out, but rather still swarm our cells early in ontogeny. Their actions can seriously damage the genome of the nascent embryo and cause sporadic diseases and infertility. Recently, we discovered a mechanism by which neighboring cells actively remove pluripotent cells that fail to undergo silencing of their endogenous retrotransposons. Our hypothesis is that there is a conditional policing mechanism reminiscent of a primitive immune system. We propose that pluripotent stem cells sense the endogenous retroviral load of their neighboring cells and, if it is higher than their own, act to kill and remove the overloaded cells. Upon completion of the outlined work, we will have (i) probed a previously unexplored sensing mechanism that involves cells “sniffing” one another for endogenous retroviruses and the removal of cells that failed to silence their genetic parasites (Aims 1 and 2) and (ii) tested whether this system is tunable and subject to immune modulation (Aim 3). These outcomes will have a positive impact because they will force us to shift our attention away from solely cell-intrinsic defense strategies towards considering a much more nuanced system in which cells constantly monitor one another for endogenous retrotransposon-related health. Our line of investigation will provide new targets for genetic diagnosis and interventions targeting pregnancy loss and infertility.