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How to Read the Chromatin Past
Vincenzo Pirrotta
Science 337, 919 (2012);
DOI: 10.1126/science.1227684
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Earth system “resilience,” would be viewed
as an emergent and evolving property of the
climate system, rather than as a constant.
The long-standing mystery of the late
Pleistocene ice ages illustrates how a constant/universal linearization of global temperature versus radiative forcing can provide
an overly narrow view of climate-adjustment
processes. These climate cycles were clearly
paced by a slowly evolving insolation field
that did not produce significant global average
radiative anomalies (at least under the usual
assumption of a globally uniform response
time). Crucially, this insolation forcing was
only effective because of strong radiative
feedbacks, including changes in atmospheric
CO2 levels. The emergence of these feedbacks
appears to have been strongly conditional on
the prevailing climate state (11) and may have
also depended on the occurrence of abrupt
(“irreversible”) transitions in regional climate
and the ocean circulation (12).
The tiered time and space scales involved
in these global climate upheavals underline
the importance, for understanding and predicting long-term climate change, of considering the full spectrum of response times in
the climate system and their interaction. An
exclusive consideration of the highest (e.g.,
decadal) register of climate variability might
be adequate for most political time frames
and may suit the urgency of immediate mitigation and adaptation challenges. However,
it falls short of the wider scientific challenge
that faces humanity, as well as a moral horizon that extends much farther into the future.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
References and Notes
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2.
3.
4.
R. Knutti, G. C. Hegerl, Nat. Geosci. 1, 735 (2008).
S. Arrhenius, Philos. Mag. J. Sci. 41, 237 (1896).
G. S. Callendar, Q. J. R. Meteorol. Soc. 64, 223 (1938).
S. Solomon et al., Eds., Climate Change 2007: The Physical Science Basis. Contribution of Working Group I to the
Fourth Assessment Report of the Intergovernmental Panel
on Climate Change (Cambridge Univ. Press, Cambridge
and New York, 2007).
18.
J. Hansen et al., Open Atmos. Sci. J. 2, 217 (2008).
M. Crucifix, Geophys. Res. Lett. 33, L18701 (2006).
E. N. Lorenz, Quat. Res. 6, 495 (1976).
C. Wissel, Oecologia 65, 101 (1984).
Tipping points need not be globally catastrophic. A longterm irreversible transition can be composed of a series of
spatially or temporally local tipping points (e.g., in land
cover, ice-sheet stability, or ocean circulation). The irreversibility of such transitions is not absolute, but defined
relative to the duration of the triggering perturbation.
I. M. Held, Bull. Am. Meteorol. Soc. 86, 1609 (2005).
D. Paillard, Rev. Geophys. 39, 325 (2001).
G. H. Denton et al., Science 328, 1652 (2010).
J. A. Higgins, D. P. Schrag, Earth Planet. Sci. Lett. 245,
523 (2006).
M. I. Hoffert, C. Covey, Nature 360, 573 (1992).
P. Köhler et al., Quat. Sci. Rev. 29, 129 (2010).
M. Pagani et al., Science 314, 1556 (2006).
M. Pagani, Z. Liu, J. LaRiviere, A. C. Ravelo, Nat.
Geosci. 3, 27 (2010).
J. Rogelj, M. Meinhausen, R. Knutti, Nature Clim. Change
2, 248 (2012).
Supplementary Materials
www.sciencemag.org/cgi/content/full/337/6097/917/DC1
Table S1
10.1126/science.1224011
MOLECULAR BIOLOGY
How to Read the Chromatin Past
Several mechanisms are used by cells to
maintain specific histone modifications and
gene activity through successive cell divisions.
Vincenzo Pirrotta
I
t has become common parlance to refer to
all histone modifications as “epigenetic,”
meaning that they carry information about
how to use the associated DNA sequences as
a function of earlier events. However, some
histone modifications, such as methylation of histone H3 at lysine 27 (H3K27), are
more epigenetic than others in that they can
self-renew from one cell cycle to the next,
thereby establishing a “cellular memory” of
earlier events. A series of articles in the past
3 years—including one by Yuan et al. (1) on
page 971 of this issue—has revealed several
subtle mechanisms by which the Polycomb
repressive complex 2 (PRC2), which methylates H3K27, reads the preexisting chromatin
state to ensure that it is faithfully maintained
after cell division (2–7).
PRC2 is one of two complexes involved
in establishing and maintaining the Polycomb-repressed chromatin state [for a review,
see (8)]. It produces H3K27 trimethylation
(H3K27me3), the characteristic mark associated with Polycomb repression. H3K27me3
stabilizes the binding of the PRC1 and directs
its action to the target gene. Both PRC comMolecular Biology and Biochemistry, Rutgers University,
604 Allison Road, Piscataway, NJ 08854, USA. E-mail:
[email protected]
plexes are recruited to target genes by various mechanisms ranging from DNA-binding factors at Polycomb response elements to
long noncoding RNAs (1). Both complexes
receive stabilizing inputs by the presence of
H3K27me3: PRC1 through the presence of
the Polycomb protein with its H3K27me3binding chromodomain and PRC2 through
recognition of H3K27me3 by its ESC component (mammalian Eed) (2).
PRC2 has the job of recognizing the previous state of the chromatin and maintaining it after cell division. Two examples clarify what is involved. One is the classical
maintenance of a Polycomb-repressed state.
Although genes can switch from a repressed
to an active state in response to specific activators, Polycomb-repressed genes tend to stay
repressed from one cell cycle to the next. This
implies that the PRC2 complex can sense
what regions contain H3K27me3 from the
previous round. The other example is one in
which a gene adjacent to a Polycomb-silenced
gene is in the active state. What prevents
Polycomb silencing from spreading into the
adjacent active gene and silencing it as well?
One answer might be that the active chromatin state antagonizes the establishment of the
repressed state. This behavior is well known
in the Drosophila early embryo where, when
Polycomb repression becomes functional, it
silences Hox genes where they are inactive
but does not interfere with them when they
are actively transcribed.
To understand how PRC2 recognizes and
maintains both repressive and active chromatin states, one must consider the components and properties of the PRC2 complex. Although the methyltransferase is the
E(Z) protein (mammalian Ezh1 and Ezh2)
with its SET domain as the catalytic center, E(Z) by itself has no activity. It needs
to be associated at least with the ESC/EED
and SU(Z)12/Suz12 components and, for
optimal activity, with the histone chaperone
variously called NURF55/CAF1/RbAp48
because of its multiple roles (1). These three
noncatalytic components position the complex on the nucleosome, read input signals,
and allosterically modulate the methyltransferase activity of E(Z).
At least three PRC2 core components are
involved in binding to a nucleosome and identifying histone H3 as the target. The NURF55
component binds to the N-terminal tail of
histone H3 protruding from the nucleosome,
helping to position the complex on its substrate (6). The N-terminal tail of histone H3
is the site of numerous possible modifications.
One of these, H3K4me3, is associated with
www.sciencemag.org SCIENCE VOL 337 24 AUGUST 2012
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919
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PERSPECTIVES
PERSPECTIVES
920
H3 a.a. 35–42
H3K27me2, me3
Stimulate
NURF55
SU(Z)12
VEFS
E(Z)
ESC
PRC2
SET
H3K4me3
H3K27me3
H3K36me2, me3
Inhibit
Feedback and feed-forward on PRC2 activity. The
structure of PRC2 is illustrated schematically. It is not
known whether any of the four core components—
NURF55, SU(Z)12, E(Z), and ESC—are present in
more than one copy. E(Z) (mammalian Ezh2) is the
enzymatically active methyltransferase. When it acts
on a target nucleosome (bottom), it receives inhibitory signals from methylation (me) states at histone
H3 lysine 4 (K4) and lysine 36 (K36). It also receives
powerful activating inputs from neighboring nucleosomes (top), again from H3 region 35–42 and from
the presence of methylation at lysine 27 (K27). a.a.,
amino acids.
because transcriptional activity and its associated features destabilize nucleosomes.
The work of Yuan et al. (1) shows that,
when nucleosomes are tightly packed, the
PRC2 complex bound to a target nucleosome senses a neighboring nucleosome by
recognizing its histone H3. Again, this triggers a conformational shift that is transmitted to the catalytic domain of E(Z), resulting
in much higher methylating activity on the
target nucleosome. The key is the SU(Z)12
component, which binds amino acids 35
to 42 of histone H3. Adding the H3 35–42
peptide to a reaction suffices to stimulate
the methylation activity on a low-density
nucleosome target. The SU(Z)12 region that
binds the peptide is once again the VEFS
region that interacts with E(Z), and the fact
that the 35–42 peptide includes lysine36
strongly suggests that this is also the region
that senses the lysine 36 methylation status.
There are, to be sure, many difficulties
to be resolved in these emerging pictures of
PRC2. One is how the same VEFS domain
of SU(Z)12 is able to interact with H3K4
and H3K36 on the same H3 molecule that
is methylated by E(Z) and at the same time
sense the nucleosome density by interacting
with another nucleosome, all while interacting with E(Z). This seems like a contorsionist’s nightmare although, very likely, PRC2
contains two copies of some or all of its components. Another fascinating structural question is how the various inputs are transmitted to E(Z) and converted into independent
allosteric rearrangements that alter the catalytic activity of its SET domain. Understanding this will probably require solving the
structure of the interfaces between E(Z) and
SU(Z)12 and ESC.
There remains a nagging question in these
and other studies on PRC2 function. What
PRC2 function is chiefly targeted by these
various mechanisms? The general assumption is that it is the function associated with
Polycomb repression of specific target genes.
This is the best-known function of PRC2 and
clearly benefits from a self-renewal mechanism. A much less well understood role of
PRC2 is the genome-wide H3K27 dimethylation that it appears to produce by a hit-andrun mechanism. The result is to dimethylate
H3K27 at all sites except those that contain
H3K27me3 and those that are transcriptionally active. It is this function that might otherwise operate in transcribed regions and that
is inhibited by the negative effects of H3K4
and H3K26 methylation and of low nucleosome density. Remarkably, this global function of PRC2 would mean that the feedback
and feed-forward mechanisms can provide
not only the self-renewal of the repressive
H3K27me3 mark but also a memory of a
region’s transcriptional activity since the loss
of H3K27 dimethylation would tend to persist in the next cell cycle and favor another
round of transcriptional activity. More work
is needed to understand this role of PRC2.
Meanwhile, PRC2 provides a clear example of the epigenetic nature of at least some
histone modifications.
References
1.
2.
3.
4.
5.
6.
7.
8.
W. Yuan et al., Science 337, 971 (2012).
R. Margueron, D. Reinberg, Nature 469, 343 (2011).
K. H. Hansen et al., Nat. Cell Biol. 10, 1291 (2008).
C. Xu et al., Proc. Natl. Acad. Sci. U.S.A. 107, 19266
(2010).
W. Yuan et al., J. Biol. Chem. 286, 7983 (2011).
F. W. Schmitges et al., Mol. Cell 42, 330 (2011).
R. Margueron et al., Nature 461, 762 (2009).
C. S. Ketel et al., Mol. Cell. Biol. 25, 6857 (2005).
24 AUGUST 2012 VOL 337 SCIENCE www.sciencemag.org
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Nucleosomes
10.1126/science.1227684
CREDIT: P. HUEY/SCIENCE
the promoter region of transcriptionally active
genes. H3K4me3 interferes with the binding
of NURF55. This is not a major loss because
SU(Z)12 also binds to histone H3. Even in the
absence of NURF55, a domain near the C-terminal region of SU(Z)12 called VEFS binds
to the N-terminal region of H3 (6). VEFS is
also the interface that interacts with E(Z) (1).
When the lysine 4 of histone H3 is trimethylated, it causes a conformational change that
is transmitted to E(Z) and affects its catalytic domain, called the SET domain, greatly
reducing its ability to release the H3 substrate.
Thus, H3K4me3 present on active genes prevents turnover and reduces the methylation
activity of PRC2 (see the figure).
SU(Z)12 recognizes another modification of histone H3 that is associated with
transcriptionally active genes: methylation
of lysine 36 (5, 6). When the target histone
H3 is di- or trimethylated at lysine 36, the
effect is again transmitted to the catalytic
domain of E(Z) and its methylation activity is reduced. As a consequence, H3K4me3
and H3K36me2/me3 strongly inhibit PRC2
methylation of H3 lysine 27 in genes that
have been recently transcribed.
Other signals tell PRC2 where to be particularly active (see the figure). One is the prior
presence of H3K27 methylation in a chromatin neighborhood. Structural studies of the
ESC/EED component revealed an aromatic
pocket formed by contributions from different
parts of the protein (2). This aromatic pocket
binds methylated lysines and, in particular,
binding of histone H3 di- or trimethylated at
lysine 27 triggers a conformational change
that is somehow transmitted to E(Z), strongly
enhancing its catalytic activity. Unlike the
H3K4me3 and H3K36me2/me3 marks,
which have to be on the same histone H3 to be
methylated, the H3K27me3 mark must be on
a separate molecule. Consequently, chromatin
regions that already contain H3K27 methylation are preferential targets for new methylation. This is the situation that prevails when
a gene repressed by Polycomb is replicated:
the old methylated histones are partitioned
between the two daughter chromatin strands,
and new, unmethylated histones are deposited
to restore the full nucleosome complement. To
ensure the maintenance of the H3K27 methyl
mark, these new nucleosomes must be preferentially targeted by PRC2. This is ensured
by the presence of neighboring nucleosomes
already bearing H3K27 methylation.
Another device that helps to the same end
does not rely on histone modifications but on
nucleosome density. Transcriptionally active
chromatin has a lower nucleosome density
because the linker histone H1 is absent and