Article

Cancer-Related Epigenome Changes Associated with Reprogramming to Induced Pluripotent Stem Cells

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Cancer Research (Impact Factor: 9.28). 10/2010; 70(19):7662-73. DOI: 10.1158/0008-5472.CAN-10-1361
Source: PubMed

ABSTRACT The ability to induce pluripotent stem cells from committed, somatic human cells provides tremendous potential for regenerative medicine. However, there is a defined neoplastic potential inherent to such reprogramming that must be understood and may provide a model for understanding key events in tumorigenesis. Using genome-wide assays, we identify cancer-related epigenetic abnormalities that arise early during reprogramming and persist in induced pluripotent stem cell (iPS) clones. These include hundreds of abnormal gene silencing events, patterns of aberrant responses to epigenetic-modifying drugs resembling those for cancer cells, and presence in iPS and partially reprogrammed cells of cancer-specific gene promoter DNA methylation alterations. Our findings suggest that by studying the process of induced reprogramming, we may gain significant insight into the origins of epigenetic gene silencing associated with human tumorigenesis, and add to means of assessing iPS for safety.

Download full-text

Full-text

Available from: William Matsui, Dec 25, 2013
0 Followers
 · 
153 Views
  • Source
    • "Additional promoter methylation profiles in IMR90 cell lines were obtained from GRO ID: GSM868008[22], GEO ID: GSM739940[23], and GEO ID: GSM375442[24]. They were compared with IMR90 promoter methylation profile, GEO ID: "
    [Show abstract] [Hide abstract]
    ABSTRACT: miRNA regulation of target genes and promoter methylation were known as primary epigenetic regula- tion of gene expression. However, how they cooperatively regulate gene expression was not discussed extensively. We found that promoter methylation was miRNA-targeting-specific. In other words, promoter methylation of genes was significantly correlated to miRNAs which target the genes. It was also found that miRNA-targeting-specific pro- moter hypomethylation was related to the miRNA regulation of target genes; the genes with miRNA-targeting-specific promoter hypomethylation were downregulated during cell senescence and upregulated during differentiation.
  • Source
    • "In the context of the above chromatin relationships, we examined the expression of the U2OS-hypermethylated genes versus ESCs, MSCs, and osteoblasts using previous (Ohm et al. 2010) and present Agilent whole-genome expression arrays. Each bottom panel in Figure 3 compares the expression between U2OS and either ESCs, MSCs, or osteoblasts for U2OS-hypermethylated genes marked by the different chromatin marks in the latter cell types. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Many DNA-hypermethylated cancer genes are occupied by the Polycomb (PcG) repressor complex in embryonic stem cells (ESCs). Their prevalence in the full spectrum of cancers, the exact context of chromatin involved, and their status in adult cell renewal systems are unknown. Using a genome-wide analysis, we demonstrate that ~75% of hypermethylated genes are marked by PcG in the context of bivalent chromatin in both ESCs and adult stem/progenitor cells. A large number of these genes are key developmental regulators, and a subset, which we call the "DNA hypermethylation module," comprises a portion of the PcG target genes that are down-regulated in cancer. Genes with bivalent chromatin have a low, poised gene transcription state that has been shown to maintain stemness and self-renewal in normal stem cells. However, when DNA-hypermethylated in tumors, we find that these genes are further repressed. We also show that the methylation status of these genes can cluster important subtypes of colon and breast cancers. By evaluating the subsets of genes that are methylated in different cancers with consideration of their chromatin status in ESCs, we provide evidence that DNA hypermethylation preferentially targets the subset of PcG genes that are developmental regulators, and this may contribute to the stem-like state of cancer. Additionally, the capacity for global methylation profiling to cluster tumors by phenotype may have important implications for further refining tumor behavior patterns that may ultimately aid therapeutic interventions.
    Genome Research 03/2012; 22(5):837-49. DOI:10.1101/gr.131169.111 · 13.85 Impact Factor
  • Source
    • "Failure will result in abnormal phenotypes (Mikkelsen et al., 2008). DNA methylation changes during reprogramming must occur in important developmental and oncogenic regions, which increases the oncogenic risk of the reprogrammed cells (Doi et al., 2009; Ohm et al., 2010). There is an additional risk for abnormalities and high tumorigenic potential, especially if c-myc is used as one of the transcription factors (Okita et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human embryonic stem cells (hESC) and induced pluripotent stem cells (hiPSC) are an attractive cell source for regenerative medicine. These cells can be expanded to vast numbers and can be differentiated to many desired pluripotent stem cells (PSC) derived therapeutic cells. Cell replacement bears promises, but also challenges. The introduction of exogenous cells in a recipient must address several different topics; its safety, the exclusion of tumor formation, the immunological response and possible rejection, the cells cleanliness and their biological quality, and quantity representing the functionality of the PSC derived therapeutic cells. Tumor formation requires the removal of any PSC remaining after differentiation. Immunological rejection can be addressed with immunomodulation of the cells and the recipient. Cleanliness can be optimized using good manufacturing practice quality systems. At last, the functionality of the cells must be tested in in vitro and in animal models. After addressing these challenges, precise strategies are developed to monitor the status of the cells at different times and in case of undesired results, corresponding counteracting strategies must exist before any clinical attempt.
    Frontiers in Physiology 02/2012; 3:19. DOI:10.3389/fphys.2012.00019 · 3.50 Impact Factor
Show more