Aberrant DNA methylation in ES cells.
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.
Department of Developmental Biology and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Guy
G
Ludwig
Department of Developmental Biology and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Deborah
D
Nejman
Department of Developmental Biology and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Merav
M
Hecht
Department of Developmental Biology and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Shari
S
Orlanski
Department of Developmental Biology and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Monther
M
Abu-Remaileh
Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
Ofra
O
Yanuka
Department of Biochemistry and Molecular Biology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Oded
O
Sandler
Department of Biochemistry and Molecular Biology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Amichai
A
Marx
Agilent Technologies, Inc., Agilent Laboratories, Santa Clara, California, United States of America.
Douglas
D
Roberts
Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
Nissim
N
Benvenisty
Department of Developmental Biology and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Yehudit
Y
Bergman
Department of Biochemistry and Molecular Biophysics, Columbia College of Physicians and Surgeons, New York, New York, United States of America.
Monica
M
Mendelsohn
Department of Developmental Biology and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Howard
H
Cedar
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D018899:CpG Islands; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D044127:Epigenesis, Genetic; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL