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Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells

2011; Nature Portfolio; Volume: 471; Issue: 7336 Linguagem: Inglês

10.1038/nature09798

1476-4687

Ryan Lister, Mattia Pelizzola, Yasuyuki S. Kida, R. David Hawkins, Joseph R. Nery, Gary C. Hon, Jessica Antosiewicz‐Bourget, Ronan C. O’Malley, Rosa Castanon, Sarit Klugman, Michael Downes, Ruth T. Yu, Ron Stewart, Bing Ren, James A. Thomson, Ronald M. Evans, Joseph R. Ecker,

Epigenetics and DNA Methylation

Induced pluripotent stem cells (iPSCs) offer immense potential for regenerative medicine and studies of disease and development. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem (ES) cells. However, it remains unknown how complete the reestablishment of ES-cell-like DNA methylation patterns is throughout the genome. Here we report the first whole-genome profiles of DNA methylation at single-base resolution in five human iPSC lines, along with methylomes of ES cells, somatic cells, and differentiated iPSCs and ES cells. iPSCs show significant reprogramming variability, including somatic memory and aberrant reprogramming of DNA methylation. iPSCs share megabase-scale differentially methylated regions proximal to centromeres and telomeres that display incomplete reprogramming of non-CG methylation, and differences in CG methylation and histone modifications. Lastly, differentiation of iPSCs into trophoblast cells revealed that errors in reprogramming CG methylation are transmitted at a high frequency, providing an iPSC reprogramming signature that is maintained after differentiation. Epigenomic reprogramming of somatic cells to produce iPS (induced pluripotent stem) cells has important therapeutic potential and is the basis of potentially important disease models. Recent reports that the reprogramming and in vitro culture of iPS cells can induce genetic and epigenetic abnormalities raise concerns over the implications of these abnormalities for clinical applications of iPS cells. Three papers in this issue present genomics studies of human iPS and embryonic stem (ES) cells, and taken together, the results confirm that chromosomal, subchromosomal and single-base level anomalies do accumulate in iPS cells. Hussein et al. compare copy number alterations of early and intermediate passage human iPS cells and report a higher level of copy number variations associated with reprogramming. During moderate length culture, however, iPS cells undergo a selection process leading to a decreased mutation load equivalent to that seen in ES cells. Gore et al. report protein-coding point mutations in 22 human iPS cell lines reprogrammed using five different methods; some mutations were pre-existing in the somatic cells, others were new mutations linked to reprogramming. Lister et al. used whole-genome DNA methylation profiling of human ES, iPS and somatic progenitor cell lines to reveal 'hotspots' in the genomes of iPS cells that are aberrantly reprogrammed. Reprogramming of somatic cells to induce pluripotent cellular properties that closely resemble those of embryonic stem (ES) cells has important therapeutic potential. The first whole genome single-base resolution profiling of the DNA methylomes of several human ES cell, induced pluripotent stem cell (iPSC) and somatic progenitor lines shows that iPSCs are fundamentally distinct from ES cells, insofar as they manifest common, quantifiable epigenomic differences. These 'hotspots of aberrant reprogramming' might be potentially useful as diagnostic markers for incomplete iPSC reprogramming, for the characterization of the efficacy of different reprogramming techniques, and for screening the potential propagation of altered methylation states into derivative differentiated cells.