Research Institute of Molecular Pathology (IMP), The Vienna Biocenter, Dr Bohrgasse7, A-1030 Vienna, Austria
* Author for correspondence (e-mail: jenuwein{at}nt.imp.univie.ac.at)
![]() |
Introduction |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Acetylation (Roth et al.,
2001) and arginine methylation
(Stallcup, 2001
) have been
linked mainly with transcriptional stimulation. Phosphorylation
(Cheung et al., 2000a
) instead
is a marker for activation of immediate early genes and a signal for mitotic
chromatin condensation. Here, we focus on histone lysine methylation. The
roles of acetylation, phosphorylation and methylation are summarized in
Table 1, and discussion of the
interplay between these distinct modifications can be found elsewhere
(Zhang and Reinberg, 2001
;
Berger, 2002
;
Kouzarides, 2002
).
|
![]() |
The complexity of histone lysine methylation |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The mammalian Suv39h enzymes and their S. pombe homologue, Clr4,
were the first histone lysine methyltransferases (HMTases) identified
(Rea et al., 2000). The
conserved SET-domain of the Su(var)3-9-related HMTases catalyzes the
methylation of H3-K9, creating a high-affinity binding site for the
chromodomain of heterochromatin protein 1 (HP1) proteins
(Lachner and Jenuwein, 2002
).
Other methylatable lysine positions might also be marked by position-specific
SET-domain HMTases for methyl-binding chromodomain proteins. The human and
mouse genomes each encode
50 predicted SET-domain proteins
(Kouzarides, 2002
) and
30
chromodomain-containing sequences (A. Schleiffer and F. Eisenhaber, personal
communication). By contrast, S. pombe has only
10 putative SET
domain HMTases, and S. cerevisiae has not more than seven
(Briggs et al., 2001
). Lysine
residues are mono-, di- and tri-methylated in vivo
(Paik and Kim, 1971
;
van Holde, 1988
;
Waterborg, 1993
). A
progressive conversion towards tri-methylation could contribute to the
apparent stability of histone lysine methylation and is ideally suited to
imparting additional layers of combinatorial control, which might allow both
short-term and long-term chromatin imprints.
The poster shows the dynamic cycle of histone lysine methylation in transcriptional stimulation or repression. `Exit routes' from this cycle reveal more extended reprogramming of the chromatin structure for example, during cellular senescence, Polycomb-mediated transcriptional memory, X chromosome inactivation and constitutive heterochromatin formation. In this `road map', the various destinations for a chromatin region are indicated by road signs that reflect distinct methylation positions and states.
![]() |
Transcriptional regulation going around with H3-K4 and H3-K9 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
H3-K9 methylation, by contrast, is present mainly in silenced chromatin
domains (Noma et al., 2001;
Litt et al., 2001
), and the
`activated genome' of S. cerevisiae exhibits abundant H3-K4
methylation but lacks apparent H3-K9 di-methylation
(Briggs et al., 2001
).
Recruitment of several H3-K9-specific HMTases induces gene repression within
euchromatin (Tachibana et al.,
2001
; Nielsen et al.,
2001
; Vandel et al.,
2001
; Ogawa et al.,
2002
; Schultz et al.,
2002
; Tachibana et al.,
2002
; Yang et al.,
2002
). G9a and a closely related enzyme appear to be euchromatic
HMTases that form complexes with HP1
and a subset of E2F transcription
factors (Ogawa et al., 2002
).
These enzymes might, by default, repress target promoters that fail to recruit
additional activating complexes.
In proliferating cells and for G9a-mediated in vivo methylation, the
repressive signal appears to be primarily H3-K9 di-methylation
(Tachibana et al., 2002) (A.
H. Peters, S. Kubicek, L. Perez-Burgos et al., unpublished), although in vitro
G9a methylates both H3-K9 and H3-K27. Differences between H3-K9 di- and
tri-methylation patterns could underpin the more robust association of
inhibitory complexes with the promoters of several cell cycle genes, as cells
enter senescence (S. Lowe, personal communication) or have their growth
potential restricted by the tumor suppressor Rb, which could recruit
additional repressive HMTases (Nielsen et
al., 2001
).
For histone lysine methylation, no `direct' demethylase has been described.
Although intermediary enzymes could destabilise the amino-methyl bond by
oxidation or radical attack (Chinenov,
2002; Falnes et al.,
2002
; Trewick et al.,
2002
), reversion of an engaged chromatin region to a more naive
state might instead be triggered by transcription-coupled histone replacement,
in which the histone H3.3 variant is deposited in place of modified histone H3
(Ahmad and Henikoff, 2002a
).
This mechanism does not operate in transcriptionally silent domains, which
might explain turnover of methylated histones in euchromatic regions while
allowing persistence of histone methylation in constitutive heterochromatin
(Ahmad and Henikoff,
2002b
).
![]() |
Polycomb and trithorax keeping on track with H3-K27 and H3-K4 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Long-term maintenance of active transcriptional states is regulated by
trx-G proteins. The trx-G proteins Trx/MLL
(Milne et al., 2002;
Nakamura et al., 2002
) and
Ash-1 each contain a SET domain and display HMTase activity. Whereas a Trx
complex performs H3-K4 di-methylation
(Czermin et al., 2002
;
Milne et al., 2002
;
Nakamura et al., 2002
), Ash-1
can methylate H3-K4, H3-K9 and probably also H4-K20
(Beisel et al., 2002
).
Ash-1-mediated methylation apparently prevents binding of the repressive PC
and HP1 proteins but facilitates association of the Brahma coactivator
(Beisel et al., 2002
)
another trx-G protein and a component of nucleosome-mobilising machines.
Indeed, H3-K4 methylation can trigger recruitment of the Brahma-related ISWI
ATPase (T. Kouzarides, personal communication). Thus, trx-G HMTases may allow
propagation of an activated chromatin state by `neutralising' repressive marks
(e.g. H3-K9 and H4-K20 methylation) (Fang
et al., 2002
; Nishioka et al.,
2002b
), while simultaneously coupling a positive signal (H3-K4
methylation) with chromatin remodelling.
![]() |
X-inactivation choosing an exit with H3-K9 and H3-K27 |
---|
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---|
![]() |
Constitutive heterochromatin a one-way street to H3-K9 tri-methylation? |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Pericentric heterochromatin is enriched in tri-methylated H3-K9. This profile is selectively abolished upon disruption of Suv39h HMTases, whereas centromeric regions display Suv39h-independent H3-K9 di-methylation (A. H. Peters, S. Kubicek, L. Perez-Burgos et al., unpublished). Interestingly, in Suv39h dn cells, pericentric heterochromatin exhibits significant H3-K9 mono-methylation (A. H. Peters, S. Kubicek, L. Perez-Burgos et al., unpublished). Suv39h HMTases are thus tri-methylating enzymes that can convert intermediary methylation states (mono- or di-methylation) into the apparently more stable tri-methylation end state. Regional H3-K9 tri-methylation at transcriptionally inert chromatin domains therefore appears to be a robust hallmark of constitutive heterochromatin.
![]() |
Outlook |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
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![]() |
Acknowledgments |
---|
![]() |
Footnotes |
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