There is recent evidence that numerous noncoding RNAs are important regulators of transcriptional and epigenetic states [82]. The noncoding RNA Xist plays a role in inducing the transcriptional inactivation of a female mammalian X chromosome [83]. In the mouse, half of the genes that resist reprogramming in nuclear transfer embryos are located on the inactive X chromosome [64,84]. These embryos aberrantly express Xist on the active X chromosome, leading to aberrant inactivation of X-linked genes [64]. In this case, resistance to gene activation is caused by the mis-regulation of a noncoding RNA that now guides the silencing machinery to chromatin. The deletion of one copy of Xist from donor nuclei is sufficient to decrease resistance and so increase the efficiency of cloned offspring derivation by nuclear transfer. It seems probable that other noncoding RNAs, short or long, may also contribute resistance to reprogramming (Table 1). One study identified a set of long noncoding RNAs upregulated during reprogramming to pluripotency; one of these facilitates reprogramming [85]. Several groups have reported that interference with the RNAi machinery can significantly alter reprogramming, and that the introduction of specific miRNAs can help iPS cell derivation [58,86–88].
