Embryonic Stem Cells as a Module for Systems Biology - Systems Biology: Networks, Models, and Applications - page 310

Emerging data suggest that individual microRNAs regulate multiple
target mRNAs, increasing the network complexity of gene regulation,
especially as the number of microRNAs produced in eukaryotic cells is
now estimated to be in the thousands, not hundreds as proposed previ-
ously. That a mRNA can be targeted by multiple microRNAs also adds
to the elaborate network of gene regulation, implying that systems
biology applications will be required to determine the multiplicity of
associations between microRNAs and the gene regulatory network
[51,52] (figure 10.6).
EPIGENOMICS: EPIGENETICS AND REPROGRAMMING
The analyses of transcriptomes emphasize the central role of networks
of regulated genes in orchestrating development. However, there is
another level of regulation determining cell fate that is directed through
the remodeling of chromatin via the posttranslational methyl modifica-
tion of cytosine and lysine residues of histones bound to DNA [53].
During mammalian development, the activity of the genome is dynam-
ically regulated to allow selective activation and repression of different
expression programs that specify different cell types [54]. The pattern
of some of the modifications to histones can be retained in daughter
cells after cell division and the information associated with the gene in
the mother cell can be inherited. This phenomenon is generally known
as epigenetics. Understanding the inheritance of silencing and methyl-
ation and demethylation patterns, how chromatin modification is
regulated, and the subsequent coordinated changes in gene regulation
are major goals in developmental biology. Several unanswered ques-
tions remain as major challenges.
Reprogramming by ES Cells
Of particular relevance to stem cell regeneration is the mechanism of
reprogramming that occurs when a somatic nucleus is transferred into
the oocyte. The oocyte environment contains active ingredients that are
sufficient to cause differentiated nuclei to revert to the zygotic state.
This is a major step in the development of therapeutic cloning.
ES cells have provided significant and relevant insights into the repro-
gramming phenomenon [55-57]. When somatic cell, such as lymphocytes,
are fused with ES cells, the resulting fusion cells take on the phenotype
and behavior of ES cells. Fusion with other cells, such as neurospheres,
gives rise to the same phenotype of ES-like cells (unpublished data).
When karyoplasts (nuclei-containing fraction of cells) or cytoplasts (cyto-
plasmic fraction of cells) are fused to neurosphere cells, it is found that
only the karyoplast can reactivate ES-specific genes in the neurosphere
cells [58]. Transcription profiling experiments indicate that the hybrid cells
resemble ES cells more closely than the differentiated fusion partner