Imprinting Found Normal in Stem Cells

Researchers have found that imprinting of genes is normal in human pluripotent stem cells and their progeny. The focus of the study, published in the July 11, 2002, online edition of the Proceedings of the National Academy of Sciences, was to determine whether human embryonic germ cells and their more specialized daughter cells would have correct imprinting and express the correct gene copy.

The process of imprinting starts in the gametes where the allele destined to be inactive in the new embryo (either the father's or the mother's as the case may be) is "marked.” The mark appears to be methylation of the DNA in the promoter(s) of the gene. Methyl groups are added to cytosines (Cs) in the DNA. This often occurs at stretches of alternating Cs and Gs called CpG islands. Methylation of promoters seems to prevent binding of transcription factors to the promoter. Although methylation seems to be the imprinting signal, keeping the gene shut down may require the production of RNA.

"The inheritance rules Mendel observed in his pea garden are not operating here,” explained Dr. Andrew Feinberg, professor of medicine at John Hopkins University (Baltimore, MD, USA). "Dominant and recessive do not explain imprinted genes. Instead, for some imprinted genes, only the copy from the mother is used, while for others, only the copy from the father is turned on--generation after generation.”

Since imprinting could not be studied directly in human cells, the investigators developed a mouse model to examine the mechanics of imprinting in differentiating cells and developing organisms. By mating males of one kind of mouse with females of another, the researchers created a set of four mouse embryonic germ cell lines in which it was possible to determine whether a gene copy was from the mother or father. With these cells, the researchers were able to study and manipulate imprinting status and observe imprinting changes as the cells differentiated.

Results of the study indicated that imprinting remained normal as the embryonic germ cells became more specialized. Earlier reports by researchers studying mouse stem cells had raised concerns that those from humans might not be properly imprinted, casting some doubt on their value for cell-based therapies. "It is reassuring to learn that the cells we have derived from primordial germ cells are imprinted normally. This is critical information for their possible safe clinical use in the future,” commented study co-author Dr. John D. Gearhart, professor of gynecology and obstetrics.



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