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Human Induced Pluripotent Stem Cells Exhibit Extensive Epigenomic Reprogramming

Bing Ren, Ph.D.
University of California, San Diego
NIEHS Grant U01ES017166

Reprogramming adult cells to regain their ability to differentiate into a variety of cells appears to leave indelible marks report NIEHS-supported researchers. When the team scoured the epigenomes of induced pluripotent stem (iPS) cells they found a consistent pattern of reprogramming errors. What's more, these incompletely reprogrammed hotspots were maintained when iPS cells were differentiated into a more specialized cell type, providing an iPS cell-specific signature enabling the researchers to determine whether a cell was an iPS or an embryonic stem cell simply by examining these hotspots.

These findings confirm that iPS cells, which by all appearances look and act like embryonic stem cells, differ in certain aspects from their embryonic cousins, emphasizing that further research will be necessary before they can be rightful substitutes for embryonic stem cells. The fact that reprogramming of somatic cells does not pose the same ethical issues as working with stem cells isolated from embryos, prompted scientists to develop iPS technology in the hope of producing cells that are just as potent as human embryonic stem cells.

Reprogramming induces a complete reconfiguration of the DNA methylation pattern throughout the genome returning it to an embryonic stem cell-like state. Overall, this process results in an iPS cell methylation pattern very similar to that of embryonic stem cells, but when the team looked further they discovered significant differences. Their experiments revealed considerable variability between iPS cell lines, including a memory of their tissue of origin. Regardless of their individual history, iPS cells showed a common defect -- hotspots near telomeres and centromeres that proved resistant to reprogramming. Averaging more than one million bases in length, these hotspots failed to acquire the methylation pattern typical of embryonic stem cells. The research team is planning additional research to understand why these regions can't be reprogrammed to a more embryonic stem cell-like state.

Citation: Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, Antosiewicz-Bourget J, O'Malley R, Castanon R, Klugman S, Downes M, Yu R, Stewart R, Ren B, Thomson JA, Evans RM, Ecker JR. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature. 2011 Mar 3;471(7336):68-73.

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