Biomedical Engineering Reference
In-Depth Information
6 Epigenetics in ESCs
Epigenetics encompasses heritable regulation that is not encoded in the DNA
sequence. Epigenetic information may persist over multiple rounds of cell
division. Stochastic and environment-induced epigenetic defects are associated
with cancer and aging. Several types of epigenetic inheritance systems are
involved in retaining ''cellular memory'' (Ng and Gurdon, 2008). One of the
mechanisms is chromatin remodeling with DNA methylation and histone
modification (Gan et al., 2007). Chromatin structures play a crucial role for
DNA accessibility, which is essential for DNA repair, DNA replication, and
gene transcription (Li et al., 2007a).
As noted above, recent technical developments, such as ChIP-ChIP and
ChIP-seq, have converted epigenetic research into a high-throughput format
to assemble ''Chromatin state maps'' that describe the genome-wide distribu-
tion of chromatin modifications (Mendenhall and Bernstein, 2008). A recent
analysis reveals a highly dynamic association of chromatin in pluripotent cells,
as compared with that of differentiated cell types (Boyer et al., 2006a).
Genome-wide histone methylation of ESCs has been characterized by
several large-scale studies (Ananiev et al., 2008; Barski et al., 2007; Bernstein
et al., 2005; Gitan et al., 2002; Guenther et al., 2007; Ikegami et al., 2007; Kim
et al., 2005; Mikkelsen et al., 2007; Shiota et al., 2002). Two distinct histone
modifications, H3K4me3 and H3K36me3, are known to be related to RNA
polymerase II initiation and transcriptional elongation, respectively (Spar-
mann and van Lohuizen, 2006). The map of H3K36me3 is strongly correlated
with RNA expression, whereas not all promoters associated with H3K4me3
are active in ESCs. H3K4me3 marks are not only seen in CG-rich promoters
of many ubiquitously expressed housekeeping genes, but also found to corre-
spond to developmental regulators and signaling protein genes that are not
expressed in ESCs. Interestingly, these inactive promoters with H3K4me3
marks also bear the repressive H4K27me3 mark, forming the ''bivalent''
state (Bernstein et al., 2006; Boyer et al., 2006b). Silencing activity seems
dominant over activation at ''bivalent'' targets. About 22% of CpG-rich
promoters are bivalently marked in mESCs. However, bivalent marks are
reduced upon terminal differentiation, resolving into single marks or no
identified marks. In committed cells, inactive genes are often marked by
H3K27me3, rather than bivalent signatures, perhaps in association with line-
age choice and commitment. Bivalent marks have been proposed to provide
flexibility in the decision of a gene to be activated or repressed. The ''bivalent''
chromatin state may poise genes for the subsequent activation during lineage-
specific differentiation. In this sense, the ''poised state'' has been suggested to
be critical for maintaining the pluripotency in ESCs. The extent to which the
''bivalent'' state is a distinctive characteristic of ESCs (or other stem cells), as
opposed to other cell types, and to which it is an essential component in
maintenance of pluripotency are unresolved.
