limited to its assembly into the MLL core complex, but rather it is a ubiquitously
expressed protein that has been identified in other chromatin-associated complexes,
including the ATAC and NSL histone acetyltransferase complex [212, 213],
and associates with the chromodomain helicase DNA-binding protein 8 (CHD8)
nucleosome-remodeling enzyme [214]. It is highly likely that the WDR5 histone
H3-binding function is integral to its role in these complexes. The epigenetic
regulation of this binding activity by arginine methylation may, therefore, have
significant downstream consequences through a number of chromatin-mediated
pathways. WDR5 was also recently reported to play a role in bladder cancer by
mediating the transcription of cyclin B1, cyclin E1, cyclin E2, UHMK1, MCL1,
BIRC3, and Nanog by H3K4me3 suggesting that this reader can be a potential
biomarker and therapeutic target for the treatment of bladder cancer [215].
5.2 Methyllysine-Specific Recognition by EED
The axial site on the top of the β-propeller is also the site of histone binding by
the EED subunit of Polycomb Repressive Complex 2 (PRC2). However, in this
case, an aromatic cage senses the methylation state of lysine residues [216]. The
PRC2 multiprotein complex is a member of the Polycomb group and functions by
copying repressive histone lysine methylation marks from one histone tail to another
[217]. This facilitates the spreading of a repressive domain within one cell or
copying it into a new daughter cell to control the genetic program [218]. The copying
of chromatin domains is needed to ensure the correct development of multicellular
organisms but often goes awry in diseases such as cancer [219]. How PRC2
recognizes existing repressive lysine marks and then makes a faithful copy of
them to newly formed histones is now beginning to be understood. The PRC2
complex consists of five core subunits: histone-lysine N-methyltransferase EZH2
(enhancer of zeste homolog 2; also known as KMT6), which contains the catalytic
SET domain, SUZ12 (suppressor of zeste 12 protein homolog), zinc finger protein
AEBP2 (adipocyte enhancer-binding protein 2) and two WD40 β-propellers,
EED (embryonic ectoderm development protein), and either RBBP4 or RBBP7
(see before) [220]. Similar to the transcriptional activator MLL, the EZH2 SET
domain is not very active on its own and requires the assembly with the other PRC2
subunits to methylate histone lysines [217]. The target lysine of PRC2 is histone
H3K27, to which EZH2 can add one, two, or three methyl groups. The fully
methylated histone H3K27 (H3K27me3) is the epigenetic signature that is classically associated with the repressive chromatin state [221]. However, as the field of
epigenetic research has matured, it has become clear that the role of individual marks
is more complicated, and for example, H3K27 is known to coexist with H3K4 on
bivalent promoters in ESC cells [222]. This more complex view is reflected in how
EZH2 activity within the PRC2 complex is regulated through the β-propeller protein,
EED. Given that misregulation of PRC2 activity is strongly implicated in the
molecular etiology of a range of cancer types, there has been an extensive effort to
374
G. Sbardella
expressed protein that has been identified in other chromatin-associated complexes,
including the ATAC and NSL histone acetyltransferase complex [212, 213],
and associates with the chromodomain helicase DNA-binding protein 8 (CHD8)
nucleosome-remodeling enzyme [214]. It is highly likely that the WDR5 histone
H3-binding function is integral to its role in these complexes. The epigenetic
regulation of this binding activity by arginine methylation may, therefore, have
significant downstream consequences through a number of chromatin-mediated
pathways. WDR5 was also recently reported to play a role in bladder cancer by
mediating the transcription of cyclin B1, cyclin E1, cyclin E2, UHMK1, MCL1,
BIRC3, and Nanog by H3K4me3 suggesting that this reader can be a potential
biomarker and therapeutic target for the treatment of bladder cancer [215].
5.2 Methyllysine-Specific Recognition by EED
The axial site on the top of the β-propeller is also the site of histone binding by
the EED subunit of Polycomb Repressive Complex 2 (PRC2). However, in this
case, an aromatic cage senses the methylation state of lysine residues [216]. The
PRC2 multiprotein complex is a member of the Polycomb group and functions by
copying repressive histone lysine methylation marks from one histone tail to another
[217]. This facilitates the spreading of a repressive domain within one cell or
copying it into a new daughter cell to control the genetic program [218]. The copying
of chromatin domains is needed to ensure the correct development of multicellular
organisms but often goes awry in diseases such as cancer [219]. How PRC2
recognizes existing repressive lysine marks and then makes a faithful copy of
them to newly formed histones is now beginning to be understood. The PRC2
complex consists of five core subunits: histone-lysine N-methyltransferase EZH2
(enhancer of zeste homolog 2; also known as KMT6), which contains the catalytic
SET domain, SUZ12 (suppressor of zeste 12 protein homolog), zinc finger protein
AEBP2 (adipocyte enhancer-binding protein 2) and two WD40 β-propellers,
EED (embryonic ectoderm development protein), and either RBBP4 or RBBP7
(see before) [220]. Similar to the transcriptional activator MLL, the EZH2 SET
domain is not very active on its own and requires the assembly with the other PRC2
subunits to methylate histone lysines [217]. The target lysine of PRC2 is histone
H3K27, to which EZH2 can add one, two, or three methyl groups. The fully
methylated histone H3K27 (H3K27me3) is the epigenetic signature that is classically associated with the repressive chromatin state [221]. However, as the field of
epigenetic research has matured, it has become clear that the role of individual marks
is more complicated, and for example, H3K27 is known to coexist with H3K4 on
bivalent promoters in ESC cells [222]. This more complex view is reflected in how
EZH2 activity within the PRC2 complex is regulated through the β-propeller protein,
EED. Given that misregulation of PRC2 activity is strongly implicated in the
molecular etiology of a range of cancer types, there has been an extensive effort to
374
G. Sbardella