title: Aberrant epigenetic silencing of tumor suppressor genes is reversed by direct reprogramming.
abstract: 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.
authors.affiliation: Department of Cell, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Shulamit
authors.initials: S
authors.lastname: Ron-Bigger
authors.forename: Ori
authors.initials: O
authors.lastname: Bar-Nur
authors.forename: Sara
authors.initials: S
authors.lastname: Isaac
authors.forename: Michael
authors.initials: M
authors.lastname: Bocker
authors.forename: Frank
authors.initials: F
authors.lastname: Lyko
authors.forename: Amir
authors.initials: A
authors.lastname: Eden
mesh_terms: D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics / Q000502:physiology; D044127:Epigenesis, Genetic / Q000235:genetics*; D020868:Gene Silencing / Q000502:physiology; D006801:Humans
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16