FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia

FITEAML:急性髓系白血病转座元件的功能研究

基本信息

  • 批准号:
    EP/Y030338/1
  • 负责人:
  • 金额:
    $ 161.81万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2024
  • 资助国家:
    英国
  • 起止时间:
    2024 至 无数据
  • 项目状态:
    未结题

项目摘要

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.
占人类基因组的一半以上,转座因子(TEs)提供了丰富的转录调控元件的来源,并具有调节细胞过程的潜力。存在有助于转录网络的TE的公认实例,然而这些实例是有限的,并且主要以基因座特异性方式显示。直接评估TE活动的生物学后果,并了解它们对细胞功能的影响程度,仍然是未知的。FITEAML将全面表征TE对细胞功能和表型的全基因组贡献,为它们的活性提供肥沃的土壤:急性髓性白血病(AML)。广泛的表观遗传变化是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,同时也提供了对TE的进化协同选择进行建模的绝佳机会。关注TE的三种不同生物活性我们将联合收割机基因组学、生物信息学、蛋白质组学和分子生物学技术相结合,以: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应性和表型的影响; iii)表征TE在抗肿瘤免疫应答中的作用;和iv)提供对TE调节的新颖和详细的机制见解。FITEAML的成果将填补在理解TE在细胞功能中的功能方面的巨大知识空白,并为关键问题提供基本见解:TE如何调节细胞表型并有助于基因组功能?除了揭示TE与宿主生物学之间的机制联系外,FITEAML还将证明如何将这些知识用于临床医学,并提供潜在的癌症治疗途径。

项目成果

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Ozgen Deniz其他文献

The Transcriptional Landscape of Ph+B-ALL Is Orchestrated By Long-Range Enhancer-Promoter Interactions and the Coordinated Action of Phosphorylation-Dependent and Phosphorylation-Independent Transcription Factors
  • DOI:
    10.1182/blood-2023-173435
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Han Leng Ng;Mark E Robinson;Valeria Malysheva;Ozgen Deniz;Nicholas Crump;Kadriye Nehir Cosgun;Kaiyue Helian;Mikhail Spivakov;Markus Müschen;Niklas Feldhahn
  • 通讯作者:
    Niklas Feldhahn

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