state selectivity (Table 1, see Højfeldt [2] for reviews on function and substrate
selectivities of KDMs).
Trimethylated as well as mono- and di-methylated lysines can be demethylated
by JmjC-KDMs, unlike KDM1 subfamily which cannot demethylate trimethylated
lysines due to the required formation of an imine. The mechanism of demethylation
by JmjC-KDMs requires 2OG and dioxygen as co-substrates and Fe(II) as a cofactor.
Evidence shows that demethylation is via known 2OG oxygenase catalysis in which
2OG and the substrate, followed by dioxygen, bind to the active site (Fig. 1). A
highly reactive Fe(IV)-oxo intermediate, formed through oxidative decarboxylation
of 2OG, can subsequently abstract a hydrogen atom from the N-methyl group. This
results in an unstable hemiaminal which can fragment to give demethylated lysine
and formaldehyde.
Despite the conservation in the catalytic mechanism, the preference for the degree
of methylation and the lysine position(s) on the histone tails are quite distinct for
each JmjC-KDM subfamily (Table 1, see Sect. 2.1.2). KDM2/KDM3/KDM7 subfamilies are di- and mono-Nε-methyl lysine demethylases, whereas KDM4/KDM5/
KDM6 subfamilies can demethylate tri-, di- and, in some cases, mono-Nε-methylated lysines. KDM5s, KDM6s and KDM2s are highly specific to demethylation at lysine 4 position of histone H3 (H3K4), H3K27 and H3K36 respectively,
while KDM3/4/7 can all demethylate at H3K9. KDM4A/B/C can demethylate
multiple histone substrates, including at H3K9 and H3K36, whereas KDM4D (and
proposed pseudogene KDM4E) demethylate at H3K9 [1, 3]. As the site and degree
of methylation on histones have differential effects on chromatin dynamics, recruitment of epigenetic protein complexes and transcription, the KDMs have wideranging functions.
There are approximately 30 proteins that have the JmjC-domains in humans, but
not all JmjC-containing proteins have demethylase activities (see [4] for review).
While the majority (approximately 20, Table 1) are JmjC-KDMs, some JmjCproteins are hydroxylase enzymes (e.g. FIH, JMJD4).
Functional assignments for some JmjC-proteins remain controversial, with both
hydroxylase and demethylase activities being reported (e.g. MINA53 and NO66,
JMJD5/KDM8, JMJD6). Recent work has revealed that some JmjC-KDMs can
catalyse the demethylation of methylated lysines on non-histone proteins, as well
as methylated arginines, thus extending the possibility of a much wider biological
role beyond histone lysine modulation [5–7].
In addition to the catalytic JmjC-domain, many JmjC-KDMs have ancillary
domains that are involved in recognising histone modifications (e.g. reader domains
such as PHD-finger domains or Tudor domains) or DNA-binding domains
(e.g. AT-rich interacting domains (ARID), CXXC zinc-finger domains). In some
cases, these ancillary domains can allosterically modulate the KDM catalysis and
influence substrate specificity [8, 9]. There are also biological functions of KDMs
that are independent of catalytic activity, as exemplified by Jarid2, the founding
member of JmjC-family. Jarid2 is predicted to be catalytically inactive but associates
with polycomb proteins and has essential roles in ES cell differentiation and
development [10].
Inhibitors of JmjC-Containing Histone Demethylases
223
selectivities of KDMs).
Trimethylated as well as mono- and di-methylated lysines can be demethylated
by JmjC-KDMs, unlike KDM1 subfamily which cannot demethylate trimethylated
lysines due to the required formation of an imine. The mechanism of demethylation
by JmjC-KDMs requires 2OG and dioxygen as co-substrates and Fe(II) as a cofactor.
Evidence shows that demethylation is via known 2OG oxygenase catalysis in which
2OG and the substrate, followed by dioxygen, bind to the active site (Fig. 1). A
highly reactive Fe(IV)-oxo intermediate, formed through oxidative decarboxylation
of 2OG, can subsequently abstract a hydrogen atom from the N-methyl group. This
results in an unstable hemiaminal which can fragment to give demethylated lysine
and formaldehyde.
Despite the conservation in the catalytic mechanism, the preference for the degree
of methylation and the lysine position(s) on the histone tails are quite distinct for
each JmjC-KDM subfamily (Table 1, see Sect. 2.1.2). KDM2/KDM3/KDM7 subfamilies are di- and mono-Nε-methyl lysine demethylases, whereas KDM4/KDM5/
KDM6 subfamilies can demethylate tri-, di- and, in some cases, mono-Nε-methylated lysines. KDM5s, KDM6s and KDM2s are highly specific to demethylation at lysine 4 position of histone H3 (H3K4), H3K27 and H3K36 respectively,
while KDM3/4/7 can all demethylate at H3K9. KDM4A/B/C can demethylate
multiple histone substrates, including at H3K9 and H3K36, whereas KDM4D (and
proposed pseudogene KDM4E) demethylate at H3K9 [1, 3]. As the site and degree
of methylation on histones have differential effects on chromatin dynamics, recruitment of epigenetic protein complexes and transcription, the KDMs have wideranging functions.
There are approximately 30 proteins that have the JmjC-domains in humans, but
not all JmjC-containing proteins have demethylase activities (see [4] for review).
While the majority (approximately 20, Table 1) are JmjC-KDMs, some JmjCproteins are hydroxylase enzymes (e.g. FIH, JMJD4).
Functional assignments for some JmjC-proteins remain controversial, with both
hydroxylase and demethylase activities being reported (e.g. MINA53 and NO66,
JMJD5/KDM8, JMJD6). Recent work has revealed that some JmjC-KDMs can
catalyse the demethylation of methylated lysines on non-histone proteins, as well
as methylated arginines, thus extending the possibility of a much wider biological
role beyond histone lysine modulation [5–7].
In addition to the catalytic JmjC-domain, many JmjC-KDMs have ancillary
domains that are involved in recognising histone modifications (e.g. reader domains
such as PHD-finger domains or Tudor domains) or DNA-binding domains
(e.g. AT-rich interacting domains (ARID), CXXC zinc-finger domains). In some
cases, these ancillary domains can allosterically modulate the KDM catalysis and
influence substrate specificity [8, 9]. There are also biological functions of KDMs
that are independent of catalytic activity, as exemplified by Jarid2, the founding
member of JmjC-family. Jarid2 is predicted to be catalytically inactive but associates
with polycomb proteins and has essential roles in ES cell differentiation and
development [10].
Inhibitors of JmjC-Containing Histone Demethylases
223