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

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内更新和维持组织。为了完成这项任务，必须保护组织干细胞免受遗传损伤。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-基因组内的重复序列，存在于所有生物体中，称为移动的DNA元件或转座元件（TE），被认为在进化过程中已经渗透到宿主基因组中。有趣的是，已经有大量的证据表明，在人类和小鼠的体细胞中，癌性转化伴随着反转录转座子的异常表达，这表明转座因子的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，如TE调控区的甲基化在沉默这些元件的活性中起着关键作用。对于TE（某类小的非编码RNA）的甲基化，“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活性的数据以及表观遗传机制抑制HSC中TE活性的相关性。因此，本提案的重点将是确定TE活性的表观遗传沉默是否对有序的HSC功能至关重要，以及Piwil蛋白和皮尔纳表达在多大程度上对HSC中TE活性的调节是必要的。

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.