FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia

转座元件(TES)占人类基因组的一半以上，为转录调控元件提供了丰富的来源，并具有调节细胞过程的潜力。有一些成熟的TES例子有助于转录网络，然而这些例子是有限的，主要以特定于基因座的方式显示。对TE活动的生物学后果的直接评估以及了解它们影响细胞功能的程度仍有待探索。FITEAML将在为其活动提供肥沃土壤的背景下，全面表征TES对细胞功能和表型的全基因组贡献：急性髓系白血病(AML)。广泛的表观遗传学改变是AML的特征，使AML成为测试TE激活对基因组功能的意义的理想模型系统，同时也提供了一个很好的机会来模拟TES的进化选择。我们将围绕TES的三个不同的生物学活性(致癌、肿瘤抑制和免疫原性)，结合基因组学、生物信息学、蛋白质组学和分子技术来：i)全面鉴定TE衍生的顺式调控序列并确定其对转录网络的影响；ii)评估其靶向操作对细胞适合性和表型的影响；iii)表征TES在抗肿瘤免疫反应中的作用；以及iv)对TE的调控提供新颖和详细的机制见解。FITEAML的结果将填补在理解TES在细胞功能中的功能方面的一大知识空白，并为关键问题提供基本的见解：TES如何调节细胞表型并对基因组功能做出贡献？除了揭示TES和宿主生物学之间的机制联系外，FITEAML还将证明这些知识如何被用于临床医学，并提供一条潜在的癌症治疗路线。

Accounting for more than half of the human genome, transposable elements (TEs) provide a rich source of transcriptional modulatory elements and have potential to regulate cellular processes. There are well-established examples of TEs that contribute to transcriptional networks, however these examples are limited and mainly shown in a locus-specific manner. Direct assessment of the biological consequences of TE activities and understanding the extent to which they influence cellular functions remains unexplored. FITEAML will comprehensively characterize the genome-wide contribution of TEs to cellular function and phenotypes in a context that provides a fertile ground for their activity: acute myeloid leukaemia (AML). Widespread epigenetic changes are characteristic features of AML, making AML an ideal model system to test the significance of TE activation on genome function while also offering an excellent opportunity to model the evolutionary co-option of TEs. Focusing on three distinct biological activities of TEs (oncogenic, tumor suppressor and immunogenic) we will combine genomics, bioinformatics, proteomics and molecular techniques to: i) comprehensively identify TE-derived cis-regulatory sequences and determine their implications on transcriptional networks; ii) assess the impact of their targeted manipulation on cellular fitness and phenotype; iii) characterize the roles of TEs in anti-tumor immune responses; and iv) provide novel and detailed mechanistic insights into TE regulation. The outcomes of FITEAML will fill a large gap of knowledge in understanding the functionality of TEs in cellular function and provide fundamental insights into the key question: How do TEs modulate cellular phenotypes and contribute to genome function? In addition to revealing mechanistic links between TEs and host biology, FITEAML will prove how this knowledge could be exploited for clinical medicine and provide a potential therapeutic route in cancer.