Epigenetic reprogramming key to normal development
Somatic cell nuclear transfer (SCNT) defines the process in which a somatic cell’s nucleus is removed and then introduced into an enucleated oocyte, or egg cell. Following transfer, the nucleus is reprogrammed by factors in the oocyte such that it now possesses the ability to mitotically divide and form totipotent stem cell clones that are genetically identical to the parental nucleus. SCNT is the same technique scientists used in 1996 to create the sheep known as Dolly, the first cloned mammal, and it holds the potential to treat a wide variety of diseases. Despite its great promise, SCNT remains a very inefficient process for producing developmentally capable clones. Furthermore, the molecular mechanisms that drive reprogramming are almost completely undefined.
In a new study put forth by Chan et al., researchers use reduced representation bisulfite sequencing (RRBS) to show that genome-wide patterns of DNA methylation decrease following SCNT in a manner similar to that of a zygote after fertilization. Notably, promoters of genes normally active in gametes and the early embryo are also specifically targeted for demethylation after SCNT. On a more global scale, however, though epigenetic patterns trend toward that of a fertilized and demethylated egg cell, the reprogramming following SCNT is incomplete with many loci resistant to demethylation. The authors’ findings suggest that epigenetic reprogramming is a major contributor to cellular totipotency, and that the oocyte’s inability to completely demethylate the donor nucleus limits SCNT’s use as an artificial embryogenic system.
One question that remains is: why are somatic cells are partially resistant to demethylation? Could it be that chromatin features imparted by a somatic cell on to its nucleus inhibit an oocyte’s reprogramming factors? Only future investigation will be able to tell for certain.
Chan et al. (2012) Mouse ooplasm confers context-specific reprogramming capacity. Nat Genet. 2012 Sep;44(9):978-80. doi: 10.1038/ng.2382. Epub 2012 Aug 19.
Link to article: http://www.nature.com/ng/journal/v44/n9/full/ng.2382.html