Center for Systems Biology of Retrotransposition

描述（由申请人提供）：反转录转座子序列构成了几乎所有真核生物基因组的重要部分，并且在小鼠和男性基因组中积极繁殖。反转录转座子及其宿主代表了多层次的复杂网络系统。包括：1)复制机制。反转录转座子序列编码的蛋白质很少，因此在其繁殖的“生命周期”中与许多宿主细胞编码的蛋白质相互作用。它们为了其他目的而利用宿主体内存在的途径，以实现复制基因组并将其插入宿主基因组DNA的机械步骤。无数的宿主蛋白也会对抗转座因子的插入，并且必须被反转录转座子避开或淹没。系统生物学方法可以用来描述这些物理相互作用者之间的关系。2)目标。基因组中的每个磷酸二酯键都代表了转座子序列插入的潜在目标，然而每种类型的转座子元件在不同的基因组组织水平上都有一定程度的优先靶向性。序列本身、DNA修饰和染色质结构、宿主蛋白结合位点以及细胞核中的三维定位都可能在确定插入位点偏好方面发挥作用。这些系统级的问题值得重新考虑，利用新的高通量方法来识别反转录转座子插入位点。3)细胞类型特异性插入限制。我们还将重点关注一个非常具有挑战性和医学相关性的系统水平问题：哺乳动物宿主和LINE-1反转录转座子之间的细胞类型特异性相互作用如何特异性影响人类健康和疾病。我们将描述特定的细胞环境如何抵抗或变得适合转座子，并解决诸如“为什么LINE-1逆转录转座子插入在结肠癌中很常见，而在其他肿瘤类型中较少？”4)宿主进化。相对于这些基因组入侵者，物种存在于一个动态状态，不断重新定义抵抗逆转录的机制。为了更好地理解新的逆转录转座子是如何应对挑战的，我们将在两个实验系统中评估宿主对新引入的逆转录转座子的反应的几个方面。我们还将使用哺乳动物基因进化模型来识别参与内源性反转录转座子适应性反应的正选择（多样化）位点。宿主和反转录转座子寄生虫的共同进化是反转录转座子生物学中一个重要但尚未得到充分研究的方面。一起，这些主题领域的研究人员将定义我们的反转录系统生物学中心。

DESCRIPTION (provided by applicant): Retrotransposon sequences make up a significant portion of genomes in virtually all eukaryotes, and are actively propagating in the genomes of mice and men. Retrotransposons and their hosts represent complex networked systems at several levels. These include: 1) Mechanism of replication. Retrotransposon sequences encode no to few proteins, and thus interact with many host cell encoded proteins during the 'life cycle' of their propagation. These tap into pathways existing in the host for other purposes, to achieve the mechanistic steps involved in replicating their genome and inserting it into host genomic DNA. A myriad of host proteins also counter transposable element insertions and must be evaded or overwhelmed by retrotransposons. Systems biology approaches can be used to describe relationships between these physical interactors. 2) Targeting. Each phosphodiester bond in the genome represents a potential target for insertion of a transposon sequence, and yet every type of transposable element has some degree of preferential targeting at distinct levels of genomic organization. Sequences themselves, DNA modifications and chromatin structure, host proteins binding sites, and perhaps three dimensional positioning in the nucleus may all play roles in determining insertion site preference. These system level questions merit renewed consideration that exploit new high throughput methods for identifying retrotransposon insertion sites. 3) Cell-type specific limits to insertion. We will also focus on a very challengin - and medically relevant - systems level question to answer: how cell type specific interactions between mammalian hosts and LINE-1 retrotransposon specifically impact human health and disease. We will delineate how specific cellular environments resist or become hospitable for transposition, and approach questions like 'Why are LINE-1 retrotransposon insertions common in colon cancer but less so in other tumor types?' 4) Host evolution. Species exist in a dynamic state with respect to these genomic invaders, constantly redefining mechanisms of resistance to retrotransposition. To better understand how new retrotransposon challenges are met, we will evaluate several aspects of host response to newly introduced retrotransposons in two experimental systems. We will also use models of mammalian gene evolution to identify loci under positive (diversifying) selection involved in adaptive responses to endogenous retrotransposons. The co-evolution of hosts and retrotransposon parasites represents an important yet understudied aspect of retrotransposon biology. Together, investigators in these topic areas will define our Center for Systems Biology of Retrotransposition.