**6. Conclusions and perspectives**

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

of epigenetic resetting mechanisms during cell differentiation can shed light on the development of more efficient and complete reprogramming approaches to further advance regen-

**Figure 2.** Mechanisms of epigenetic reprogramming. Epigenetic patterns in differentiated cells need to be reprogrammed to those of pluripotent cells, which results in silencing of differentiated genes and reactivation of pluripotency genes. Epigenetic reprogramming can be achieved by modulation of DNA methylation and histone modifications by various epigenetic modifying enzymes, such as Dnmt, Tet, Kdm2b, Kdm4b, Utx, Ezh2 (PcG), histone variant replacement, and chromatin remodeling enzymes. Other epigenetic mechanisms may also be involved. It is believed that a collaborative contribution of different epigenetic mechanisms is required for complete reversal of the differentiated cell state.

Resetting Cell Fate by Epigenetic Reprogramming http://dx.doi.org/10.5772/intechopen.81015 175

This work was supported by the Research Grants Council of the Hong Kong Special

Administrative Region (SAR), China (Grant no. HKU775510M and HKU774712M).

The authors declare that they have no conflict of interest.

erative medicine.

**Acknowledgements**

**Conflict of interest**

**Figure 2.** Mechanisms of epigenetic reprogramming. Epigenetic patterns in differentiated cells need to be reprogrammed to those of pluripotent cells, which results in silencing of differentiated genes and reactivation of pluripotency genes. Epigenetic reprogramming can be achieved by modulation of DNA methylation and histone modifications by various epigenetic modifying enzymes, such as Dnmt, Tet, Kdm2b, Kdm4b, Utx, Ezh2 (PcG), histone variant replacement, and chromatin remodeling enzymes. Other epigenetic mechanisms may also be involved. It is believed that a collaborative contribution of different epigenetic mechanisms is required for complete reversal of the differentiated cell state.

of epigenetic resetting mechanisms during cell differentiation can shed light on the development of more efficient and complete reprogramming approaches to further advance regenerative medicine.
