Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts

By A. Doi, In-Hyun Park, Bo Wen, Peter N. Murakami, Martin J. Aryee, Rafael A. Irizarry, Brian R. Herb, Christine Ladd-Acosta, Junsung Rho, Sabine Loewer and 4 more. Nature Genetics, 2009

1,195 citations recorded by the source corpus.

Induced pluripotent stem (iPS) cells are derived by epigenetic reprogramming, but their DNA methylation patterns have not yet been analyzed on a genome-wide scale. Here, we find substantial hypermethylation and hypomethylation of cytosine-phosphate-guanine (CpG) island shores in nine human iPS cell lines as compared to their parental fibroblasts. The differentially methylated regions (DMRs) in the reprogrammed cells (denoted R-DMRs) were significantly enriched in tissue-specific (T-DMRs; 2.6-fold, P < 10−4) and cancer-specific DMRs (C-DMRs; 3.6-fold, P < 10−4). Notably, even though the iPS cells are derived from fibroblasts, their R-DMRs can distinguish between normal brain, liver and spleen cells and between colon cancer and normal colon cells. Thus, many DMRs are broadly involved in tissue differentiation, epigenetic reprogramming and cancer. We observed colocalization of hypomethylated R-DMRs with hypermethylated C-DMRs and bivalent chromatin marks, and colocalization of hypermethylated R-DMRs with hypomethylated C-DMRs and the absence of bivalent marks, suggesting two mechanisms for epigenetic reprogramming in iPS cells and cancer.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8088aac5d699457be3fca6ac7b02acfe5e2a3df2

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A decade of exploring the cancer epigenome — biological and translational implications (2011, background): “DNA methylation patterns for conserved gene sequences several kilobases upstream or downstream of promoter CpG islands, and termed shores, are tightly linked with the tissue of origi”
Increased methylation variation in epigenetic domains across cancer types (2011, positive): “Furthermore, cDMRs are highly enriched among regions differentially methylated during stem cell reprogramming of induced pluripotent stem (iPS) cells 5 .”
Reference Maps of Human ES and iPS Cell Variation Enable High-Throughput Characterization of Pluripotent Cell Lines (2011, positive): “To quantitatively address this issue, we reframed them as a classification problem: Can we use DNA methylation and gene expression profiles to accurately predict whether a specific cell line is an ES or iPS cell line? Several gene signatures of differences between human ES and iPS cell lines have be”
Energy Metabolism in Human Pluripotent Stem Cells and Their Differentiated Counterparts (2011, background): “differing from both ESCs and differentiated cells [6] , suggesting both the occurrence of abnormal methylation during reprogram-”
Induced pluripotency: history, mechanisms, and applications. (2010, background): “At the 2252 GENES & DEVELOPMENT molecular level, gene-specific and global differences in DNA methylation (Deng et al. 2009; Doi et al. 2009; Pick et al. 2009) and in the expression of mRNAs and miRNAs (Chin et al. 2009; Wilson et al. 2009) have been reported between both mouse and human ESCs and…”
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