Department of Cell, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
Stem Cells. 2010 Aug;28(8):1349-54. doi: 10.1002/stem.468.
Direct reprogramming procedures reset the epigenetic memory of cells and convert differentiated somatic cells into pluripotent stem cells. In addition to epigenetic memory of cell identity, which is established during development, somatic cells can accumulate abnormal epigenetic changes that can contribute to pathological conditions. Aberrant promoter hypermethylation and epigenetic silencing of tumor suppressor genes (TSGs) are now recognized as an important mechanism in tumor initiation and progression. Here, we have studied the fate of the silenced TSGs p16(CDKN2A) during direct reprogramming. We find that following reprogramming, p16 expression is restored and is stably maintained even when cells are induced to differentiate. Large-scale methylation profiling of donor cells identified aberrant methylation at hundreds of additional sites. Methylation at many, but not all these sites was reversed following reprogramming. Our results suggest that reprogramming approaches may be applied to repair the epigenetic lesions associated with cancer.
直接重编程程序重置细胞的表观遗传记忆，并将分化的体细胞转化为多能干细胞。除了在发育过程中建立的细胞身份的表观遗传记忆外，体细胞还可以积累异常的表观遗传变化，从而导致病理状况。现在，异常启动子超甲基化和肿瘤抑制基因（TSGs）的表观遗传沉默被认为是肿瘤起始和进展的重要机制。在这里，我们研究了沉默的 TSG p16（CDKN2A）在直接重编程过程中的命运。我们发现，在重编程后，p16 的表达得到恢复，并且即使在诱导分化时也能稳定维持。对供体细胞的大规模甲基化分析鉴定出数百个额外位点的异常甲基化。在重编程后，许多（但不是所有）这些位点的甲基化被逆转。我们的结果表明，重编程方法可用于修复与癌症相关的表观遗传损伤。
