**Acknowledgements**

and improve the differentiation competency to other unrelated somatic lineages [120]. Interestingly, it has been demonstrated that continuous passaging of iPS cells abrogates somatic DNA methylation patterns [115], which suggests a passive replication-dependent mechanism in loss of the parental memory in iPS cells. Nevertheless, a study showed that the epigenetic memory in some iPS cell lines cannot be removed even after extended passages [124]. Apart from DNA methylation, microRNA expression pattern was also shown to have a role in the retention of somatic memory in iPS cells derived from hematopoietic progenitors [126]. However, it should be emphasized that other profiling studies of iPS cells failed to find the gene expression and epigenetic differences when compared to ES cells [127, 128]. It thus proposes that the "somatic memory" in iPS cells could be an artifact of incomplete reprogramming resulting in variation between iPS cell lines [129]. It is also possible that there are individual iPS cell lines expressing gene signatures owing to culture conditions and laboratory practices [130], similar to the scenario that some ES cell lines exhibit preferential differentiation towards specific lineages [131–133]. In summary, the epigenetic memory in

Although the term "epigenetic landscape" was first introduced by Waddington in 1942 [1], our understanding of how the epigenome of a cell type is maintained and altered during differentiation is still far from complete. The reversal of the differentiated state of a cell has important implications for our understanding of normal development and for regenerative medicine. Epigenetic reprogramming provides heritable changes of cell identity, and thus is a key event for the complete and permanent conversion of cell fate (**Figure 2**). Although reprogramming of cell fate can be achieved by different strategies, the rate (reprogramming time) and efficiency (number of reprogrammed cells) are far from comparable to the natural event during fertilization/de-differentiation. Achieving a complete epigenetic reversion to generate reprogrammed cells or iPS cells with a comparable potency state of early embryos would imply that these cells can respond correctly to differentiation-promoting signals, and more importantly, decrease the tumorigenic potential owing to pre-disposing epimutations. Notably, the status of epigenetic memory in iPS cells can be regarded as a state of incomplete reprogramming. The biased differentiation owing to the persistent somatic epigenetic memory in iPS cells might be useful in efficient differentiation to the desired cell type of origin, which usually results in a heterogeneous cell population by using un-optimized differentiation protocols. On the contrary, it has been shown that *in vitro* culture condition can alter the epigenetic status of iPS cells [134]. With an optimized culture condition, a more homogeneous population of iPS cells can be obtained, which corresponds to the naïve state of pluripotency, and hence, further abrogate the somatic "epigenetic memory". A more recent approach in reprogramming involves the use of a combination of small chemical molecules and epigenetic modifying agents, without any ectopic expression of transcription factors [135, 136]. This approach seems to induce pluripotent reprogramming process different from the transcription factor-mediated approach. Therefore, unlocking the secrets

iPS cells remains a contentious issue.

174 Chromatin and Epigenetics

**6. Conclusions and perspectives**

This work was supported by the Research Grants Council of the Hong Kong Special Administrative Region (SAR), China (Grant no. HKU775510M and HKU774712M).
