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PLoS One. 2014 May 22;9(5):e96090. doi: 10.1371/journal.pone.0096090. eCollection 2014.

Aberrant DNA methylation in ES cells.

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Department of Developmental Biology and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
Department of Biochemistry and Molecular Biology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Agilent Technologies, Inc., Agilent Laboratories, Santa Clara, California, United States of America.
Department of Biochemistry and Molecular Biophysics, Columbia College of Physicians and Surgeons, New York, New York, United States of America.


Both mouse and human embryonic stem cells can be differentiated in vitro to produce a variety of somatic cell types. Using a new developmental tracing approach, we show that these cells are subject to massive aberrant CpG island de novo methylation that is exacerbated by differentiation in vitro. Bioinformatics analysis indicates that there are two distinct forms of abnormal de novo methylation, global as opposed to targeted, and in each case the resulting pattern is determined by molecular rules correlated with local pre-existing histone modification profiles. Since much of the abnormal methylation generated in vitro appears to be stably maintained, this modification may inhibit normal differentiation and could predispose to cancer if cells are used for replacement therapy. Excess CpG island methylation is also observed in normal placenta, suggesting that this process may be governed by an inherent program.

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