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

点击翻译按钮获取中文摘要

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.