Biomedical Engineering Reference
In-Depth Information
TrxG (Trithorax-group) and PcG (polycomb-group) proteins have an
important role in cellular memory system. H3K4me3 is catalyzed by the MLL
(mixed-lineage leukemia protein) component of the TrxG complex, and
H3K27me3 is catalyzed by the Ezh1/2 component of the PRC2 (PcG 2 com-
plex) (Cao et al., 2002; Francis and Kingston, 2001; Simon and Tamkun, 2002).
The PRC2 complex contains at least four subunits, including the three PcG
proteins EZH2, EED, and SUZ12 and the histone-binding proteins RbAp48/
46. A second PcG complex, PRC1, which likely exists in many variant forms
due to a large number of homologues in mammalian cells, contains at least six
different subunits: the polyhomeotic- (HPH1-3), polycomb-/CBX (HPC1/
CBx2, HPC2/CBX4, HPC3/CBX8, CBX6, CBX7), the RING1- and 2-
(RING1A/B), the posterior sex comb- (BMI1, MEL18, MBLR, and NSPC1),
and sex comb on midleg (SCML1-2) proteins (Levine et al., 2002). PRC1 is
thought to bind methylated H3K27 and mediate stable silencing through
recruitment of DNA methylation complexes and chromatin compaction.
Gene knockout studies demonstrated the importance of PcG complexes for
proper development. Deletion of any of the PRC2 members results in embryo-
nic lethality (Faust et al., 1998; O'Carroll et al., 2001; Pasini et al., 2004).
However, EED-, Ezh2-, and SUZ12-deficient ESCs retain some degree of
pluripotency (Boyer et al., 2006b; Chamberlain et al., 2008; Morin-Kensicki
et al., 2001; Pasini et al., 2004; Shen et al., in press). These data suggest that
PRC2 may be dispensable for overall maintenance of pluripotency. PRC1
members play important role during later stage of development except Ubiqui-
tin E3 ligase Ring1b. Deletion of either EDR1 or Bmi1 results in loss of
hematopoietic stem cells. Loss of Bmi1 also impairs neural and mammary
stem cells. On the other hand, deletion of Ring1b is embryonic lethal (Voncken
et al., 2003) and Ring1b appears to be involved in maintenance of ESCs by
repressing high CpG content promoters and bivalent histone marks or active
H3K4me3 marks (van der Stoop et al., 2008)
The recent discovery of histone demethylases further highlights the flexibility
of epigenetic modifications. The UTX (ubiquitously transcribed tetratricopep-
tide repeat, X chromosome) and JMJD3 serve as H3K27 demethylases (Hong
et al., 2007; Loh et al., 2007). The Jmj C (Jumonji C)-containing JARID1
protein family including the RBP2/JARID1A (RB-binding protein 2), PLU1/
JARID1B, and SMCX/JARID1C serve as a demethylases with specificity for
tri- and dimethylated H3K4 (Christensen et al., 2007). The LSD1 (lysine-
specific demethylase1) serves as a dimethylase for mono- and dimethylated
H3K4 when in complex with CoREST to silence gene expression (Shi et al.,
2004) and serves as a demethylase for mono- and dimethylated H3K9 when in
complex with AR (androgen receptor) to promote gene activation (Metzger
et al., 2005). Jmjd1a (also known as JHDM2A (JmjC-domain-containing his-
tone demethylase2)) also demethylates H3K9 mono- and dimethylation in vitro
and functions as a coactivator for AR to demethylate chromatin of AR target
genes (Yamane et al., 2006). However, LSD1 removes the methyl group
through a flavin-adenine-dinucleotide-dependent oxidation reaction (Shi
