Aberrant Epigenetic Silencing of Tumor Suppressor Genes Is Reversed by Direct Reprogramming.

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 initiatiou and progression. Here, we have studied the fate of the silenced TSGs pl6(CDKN2A) during direct reprogramming. We find that following reprogramming, pl6 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, hut not all these sites was reversed following reprogramming. Our results suggest that reprogramming approaches may he applied to repair the epigenetic lesions associated with cancer. [ABSTRACT FROM AUTHOR]