Center for Systems Biology of Retrotransposition

描述（由申请人提供）：逆转录转座子序列构成几乎所有真核生物基因组的重要部分，并在小鼠和人类基因组中活跃繁殖。反转录转座子和它们的宿主在几个层面上代表了复杂的网络系统。这些问题包括：1）复制机制。反转录转座子序列编码没有或很少的蛋白质，因此在其繁殖的“生命周期”期间与许多宿主细胞编码的蛋白质相互作用。它们利用宿主中存在的途径用于其他目的，以实现复制其基因组并将其插入宿主基因组DNA中所涉及的机械步骤。无数的宿主蛋白质也对抗转座因子的插入，并且必须被逆转录转座子避开或压倒。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)面向.基因组中的每个磷酸二酯键代表转座子序列插入的潜在靶标，然而每种类型的转座因子在基因组组织的不同水平上具有一定程度的优先靶向。序列本身，DNA修饰和染色质结构，宿主蛋白结合位点，也许在细胞核中的三维定位都可能在决定插入位点偏好方面发挥作用。这些系统水平的问题值得重新考虑，利用新的高通量的方法来确定反转录转座子插入位点。3)细胞类型特定的插入限制。我们还将专注于一个非常具有挑战性和医学相关的系统水平问题：哺乳动物宿主和LINE-1逆转录转座子之间的细胞类型特异性相互作用如何特别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，并探讨诸如“为什么LINE-1逆转录转座子插入在结肠癌中很常见，但在其他肿瘤类型中却不那么常见？”（4）寄主进化。物种相对于这些基因组入侵者处于动态状态，不断重新定义对逆转录转座的抗性机制。为了更好地了解新的反转录转座子的挑战是如何满足的，我们将在两个实验系统中评估宿主对新引入的反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的模型，以确定积极（多样化）的选择参与内源性逆转录转座子的适应性反应的位点。宿主和反转录转座子寄生虫的共同进化代表了反转录转座子生物学的一个重要但尚未充分研究的方面。这些主题领域的研究人员将共同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.