It is important to appreciate that there are instances in which a resistance to reprogramming is not fully explained by DNA methylation alone. The inactive X chromosome of female mammalian cells is commonly associated with methylated DNA. By contrast, the inactive X chromosome of female mouse epiblast stem cells is methylated yet it can be reactivated by nuclear transfer to Xenopus oocytes, whereas the inactive X of MEFs, also methylated, is resistant to reactivation [51]. DNA methylation only restricts transcription in specific chromatin contexts [52], for example in promoters, where it may directly prevent transcription factor binding or promote DNA compaction. Furthermore, methylated plasmid DNA is perfectly well transcribed in Xenopus oocytes until it becomes chromatinised and hypoacetylated through the recruitment of histone deacetylases (Hdac) [53]. The main conclusion here is that DNA demethylation takes place during nuclear reprogramming, but is incompletely effective and so can cause resistance to successful reprogramming.
