Dissecting the role of PIWIL4 as a novel epigenetic factor in acute myeloid leukemia

剖析 PIWIL4 作为一种新型表观遗传因子在急性髓系白血病中的作用

• 批准号: 171802282
• 负责人: Professor Dr. Christian Buske
• 金额: --
• 依托单位: Institut für Experimentelle Tumorforschung
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/171802282?language=en
• 关键词: Dissecting; role; PIWIL4; novel; epigenetic

The self – renewal capacity of adult stem cells allows them to renew and maintain the tissues for the complete lifespan of the organism. For this task, it is essential for tissue stem cells to be protected from genetic damage. One potential genetic threat for tissue stem cells are some of their own genomic DNA– repetitive sequences within the genome, that are present in all organisms, called mobile DNA elements or transposable elements (TE) that are thought to have infiltrated host genomes over the evolutionary time. Interestingly, there has been extensive evidence of cancerous transformation accompanied by aberrant expression of retrotransposons in somatic cells both in human and mouse, suggesting that uncontrolled activity of transposable elements might be associated with malignant transformation. Importantly, epigenetic mechanisms such as methylation of regulatory regions of TEs play a key role in silencing the activity of these elements. For the methylation of TEs a certain class of small non-coding RNAs, the ‘piwi interacting RNAs’ (piRNAs) are essential. So far, there are no data on TE activity in hematopoietic stem cells (HSCs) and on the relevance of suppression of TE activity in HSCs by epigenetic mechanisms. Therefore, the focus of this proposal will be to determine whether epigenetic silencing of TE activity is essential for ordered HSC function and to what extent Piwil protein and piRNA expression is necessary for the regulation of TE activity in HSCs.

成体干细胞的自我更新能力使它们能够在生物体的整个生命周期中更新和维持组织。对于这项任务，保护组织干细胞免受遗传损伤至关重要。对组织干细胞的一个潜在遗传威胁是它们自身的一些基因组 DNA，即基因组内的重复序列，存在于所有生物体中，称为移动 DNA 元件或转座元件 (TE)，人们认为它们在进化过程中已渗透到宿主基因组中。有趣的是，有大量证据表明，人类和小鼠体细胞中的癌变伴随着逆转录转座子的异常表达，这表明转座元件不受控制的活性可能与恶性转化有关。重要的是，表观遗传机制（例如 TE 调控区域的甲基化）在沉默这些元件的活性方面发挥着关键作用。对于 TE 的甲基化，一类小非编码 RNA 来说，“piwi 相互作用 RNA”(piRNA) 是必不可少的。到目前为止，还没有关于造血干细胞（HSC）中 TE 活性以及表观遗传机制抑制 HSC 中 TE 活性的相关性的数据。因此，本提案的重点是确定 TE 活性的表观遗传沉默对于有序的 HSC 功能是否至关重要，以及 Piwil 蛋白和 piRNA 表达在多大程度上对于 HSC 中 TE 活性的调节是必需的。