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Human Molecular Genetics Advance Access published online on July 26, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl188
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© 2006 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received June 7, 2006
Revised July 21, 2006
Accepted July 21, 2006

Article

Abnormal CpG island methylation occurs during in vitro differentiation of human embryonic stem cells

Yin Shen 1, Janet Chow 1, Zunde Wang 2, and Guoping Fan 1 *

1 Department of Human Genetics, Institute of Stem Cell Biology and Medicine, David Geffen School of Medicine, UCLA, 695 Charles Young Drive South, Los Angeles, CA 90095
2 EpiGenX Pharmaceuticals, Inc., 5385 Hollister Ave., Santa Barbara, CA 93111

* To whom correspondence should be addressed.
Guoping Fan, E-mail: gfan{at}mednet.ucla.edu


  Abstract

Directed differentiation of human embryonic stem cells (hESCs) into specific somatic cells holds great promise for cell replacement therapies. However, it is unclear if in vitro hESC differentiation causes any epigenetic abnormality such as hypermethylation of CpG islands. Using a differential methylation hybridization (DMH) method, we identified 65 CpG islands (out of 4,608 CpG islands or 1.4%) that exhibited increased DNA methylation during the conversion of hESCs into neural progenitor/stem cells (NPCs). These methylated CpG islands belong to genes in cell metabolism, signal transduction, and cell differentiation, which are distinctively different from oncogenic CpG island hypermethylation observed in cancer-related genes during tumorigenesis. We further determined that methylation in these CpG islands, which is probably triggered by de novo DNA methyltransferase Dnmt3a, is abnormally higher in hESC-NPCs than in primary NPCs and astrocytes. Correlating with hypermethylation in promoter CpG islands of metabolic enzyme gene CPT1A and axoneme apparatus gene SPAG6, levels of CPT1A and SPAG6 mRNAs are significantly reduced in hESC-NPCs when compared to hESCs or primary neural cells. Because CPT1A is involved in lipid metabolism and CPT1A deficiency in human is associated with the hypoketotic hypoglycemia disorder, the reduced CPT1A expression in hESC-NPCs raises a potential concern for the suitability of these cells in cell transplantation. Collectively, our data show that abnormal CpG island methylation takes place in a subset of genes during the differentiation/expansion of hESC derivatives under current culture conditions, which may need to be monitored and corrected in future cell transplantation studies.


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