ESCs consistent differences are observed. Among histone modifications,

ESCs and iPS cells share
similarities in morphology, self-renew capacity, differentiation potential, and
age-affected cellular systems such as telomeres and mitochondria. However,
numbers studies comparing ESCs and iPS cells at the epigenetic,
transcriptional, proteomic and metabolic levels have demonstrated the molecular
differences between ESCs and iPS cells (Bock et al., 2011; Chin et al., 2009, 2010;
Doi et al., 2009; Ghosh et al., 2010; Kim et al., 2010b; Lister et al., 2011;
Loewer et al., 2010; Marchetto et al., 2009; Polo et al., 2010b).

            At transcriptional level, human iPS cells and ESCs can be
distinguished by their differential expression of protein-coding RNAs which
mainly attributes to the residual expression of somatic genes but dissipate
upon extended passaging (Chin et al., 2009, 2010). In addition, ten large inter­genic non-coding RNAs (lincRNAs) are
differentially expressed between human iPS cells and ESCs. Some of these
lincRNAs participate in the reprogramming process that their overexpression enhances and the
downregulation inhibits reprogramming (Loewer et al., 2010).

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transcriptional differences can result in functional differences between iPS
cells and ESCs.  For example, the
repression of a small group of non-coding RNAs encoded in the Dlk1–Dio3
gene cluster could affect the functionality of mouse iPS cells. Although
some iPS cells lacking of expression at this locus are capable of generating
chimaeras, fail the tetraploid complementation assay (the gold standard for
examining mouse pluripotency) to show animals are entirely derived from these
cells (Stadtfeld et al., 2010).

            The chromatin state of iPSCs and ESCs has been
extensively examined to date and consistent differences are observed.  Among histone modifications, genome-wide
studies showed the expression patterns for H3K4me3 and H3K27me3 are
indistinguishable between both
mouse and human iPS cells and their respective ESCs counterparts (Maherali et al., 2007; Mikkelsen et al.,
2008). However, the expression
patterns of H3K9me3 within promoter regions are different (Hawkins et al., 2010) and its overexpression were found among the genes which are
differentially expressed between human iPS cells and ESCs.

            Notably, many of the transcriptional and chromatin differ­ences
described are observed in the early-passage iPS cells and disappeared at a
later passage, suggestive of a residual ‘epigenetic memory’ persisting in
the early-passage iPS cells, reflecting the cell of
origin (Chin et al., 2009; Ghosh et al., 2010;
Marchetto et al., 2009).

            Specifically, Kim and Polo et al. provide functional
evidence showing that an epigenetic memory of cell of origin persist in mouse
iPS cells which is linked to the residual DNA
methylation within lineage-specific genes. This persisting DNA methylation
pattern influences the functionality and differentiation potential of derived
iPS cells (Kim et al., 2010; Polo et al., 2010). For example, iPS cells derived from blood cells are more easily to be
differentiated to their original blood cell lineage than fibroblast-derived
iPS. This may due to the DNA hypermethylation of blood cell markers in
fibroblast-derived iPS cells that potentially prevent their upregulation under
the induction of blood lineage differentiation. Reversely, treatments of
non-blood cell-derived iPS cells with DNA methylation inhibi­tors enable a more
efficient differentiation towards blood lineage. Notably, this residual
epigenetic memory in mouse iPS cells could be erased upon extended passaging.

            Furthermore, this epigenetic memory has been uncovered in
human iPS cells. Single-cell based whole-genome DNA methylation mapping studies
reveal that the somatic DNA methylome was only partially erased during
reprogramming and an epigenetic memory of the somatic DNA methylation pattern
persists in human iPS cells. In addition, some iPS cells fail to establish
ESC-like methylation pattern which is associated with transcriptional and
functional differences found between late-passage iPS cells and ESCs (Lister et al., 2011).

            Nevertheless, genetic abnormalities have been seen in
some iPS cells. One study suggests that these abnormalities might due to the
oncogenic stress induced by reprogramming factors. They observed a higher level
of phosphorylated histone H2AX, one of the earliest indicators of DNA
double-strand breaks, in the cells induced with OSKM or OSK. They demonstrated
that the homologous recombination pathway is essential for repair DNA
double-strand breaks to maintain genomic integrity during reprogramming process
(González et al., 2013). Nevertheless, more evidence are required to settle whether these
defects are as a result of reprogramming process or due to the genetic and
epigenetic differences existing within the individual parental fibroblasts (Abyzov et al., 2012; Cheng et al., 2012).