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First published online 3 May 2006
doi: 10.1242/dev.02402
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Meeting Review |
Institute of Human Genetics, CNRS, 141, rue de la Cardonille, 34396 Montpellier Cédex 5, France.
e-mail: giacomo.cavalli{at}igh.cnrs.fr
SUMMARY
The epigenetic regulation of chromatin structure and composition has often been studied molecularly in the context of specific DNA-dependent processes. However, epigenetics also play important global roles in shaping and maintaining cell identity, and in patterning the body plan during normal development. Moreover, alterations in epigenetic regulation are involved in many diseases, including cancer. The advances in our understanding of the impact of epigenetics in development and disease were discussed at a recent Keystone symposium.
Introduction
Epigenetics was introduced by Conrad Hal Waddington over 60 years ago as
the study of those processes involved in the unfolding of development
(Waddington, 1942
). The
discovery of the role of DNA in inheritance, and of the structure of the DNA
double helix, have cast a shadow over this discipline for decades, until it
came under the spotlight again in the 1980s with studies on chromatin
structure. Epigenetics was then redefined as the study of heritable traits
that are not dependent on the primary sequence of DNA
(Holliday, 1994). The
discovery of the importance of molecular machines that act on chromatin to
regulate gene expression has fuelled a great interest in this field. It has
recently become clear that epigenetics does not only affect the expression of
individual genes. Rather, epigenetic regulators play crucial roles in the
global shaping and maintenance of developmental patterning. This involves both
dynamic tissue- and cell type-specific changes during patterning, as well as
the maintenance of the cellular memory that is required for developmental
stability. Furthermore, when epigenetic regulation goes wrong, it can have
pathological consequences, which include immune disorders and cancer
(Feinberg et al., 2006).
Researchers are, thus, increasingly interested in approaching epigenetics from
a developmental point of view, as was well illustrated at the `Epigenetics and
Chromatin Remodelling during Development' symposium that was recently
organized by Renato Paro and Peter Fraser at Keystone (CO, USA). This meeting
highlighted the broad impact that epigenetics has on the regulation of
biological processes, much in line with Waddington's original concept, and
provided a platform for the communication of major breakthroughs in this
field.
Molecular advances in understanding chromatin structure and function
Chromatin is the folded state of genetic material in the cell nucleus.
One-hundred and forty-six basepairs of DNA wrap in 1.6 superhelical
left-handed turns around an octamer that contains two copies each of the
histones H2A, H2B, H3 and H4, to form the nucleosome. The folding of DNA into
nucleosomes affects the function of DNA-binding proteins that have to access
their target DNA surfaces. In order to regulate specific DNA-dependent
processes, chromatin can be remodelled in three different ways: by removing or
mobilizing the histones by means of ATP-dependent nucleosome remodelling
machines (Smith and Peterson,
2005); by altering chromatin structure via the post-translational
modification of histones (Strahl and
Allis, 2000); or by the replacement of specific histones
(Henikoff and Ahmad,
2005).
In recent years, the regulatory role of histone modifications, including
acetylation, methylation, ubiquitylation and phosphorylation, has emerged as a
main player in epigenetic regulatory mechanisms. Specific enzymatic machines
are able to mark individual residues of each histone, while other protein
complexes are able to read these marks and elicit specific responses
(Wang et al., 2004). One
example of the language spoken by `writers' and `readers' of histone marks in
the maintenance of chromatin states was given by David Allis (Rockefeller
University, New York, NY, USA). The proteins of the Polycomb group (PcG) and
of the trithorax group (trxG) are able to maintain silent and active,
respectively, chromatin states at many developmental genes
(Ringrose and Paro, 2004). The
action of these proteins involves the deposition and the interpretation of
multiple histone marks, such as the methylation of specific lysine (K)
residues on histone H3 (Ringrose and Paro,
2004). Histone lysines can be mono-, di- or trimethylated. One of
the main marks needed to trigger transcription is the methylation of lysine 4
on histone H3 (H3K4). The trxG proteins, called Trx in Drosophila and
MLL in vertebrates, have been shown to trimethylate H3K4
(Milne et al., 2002;
Muller et al., 2002).
Recently, the WDR5 protein was shown to act as a reader of the H3K4 di- and
trimethyl mark (Dou et al.,
2005; Wysocka et al.,
2005). The Allis group has now identified a specific reader of the
trimethyl H3K4 mark in the largest subunit of the ATP-dependent chromatin
remodelling complex called NURF [BPTF/FALZ in humans and the NURF-301/E(bx)
complex in Drosophila]. Their functional studies indicate that these
proteins do not read the dimethyl mark, but only the trimethyl mark, providing
an excellent candidate for the factors that act downstream of Trx/MLL to
propagate active chromatin states (C. D. Allis, personal communication). The
co-crystal structure of a region of NURF-301 bound to an H3 peptide that
carries a trimethyl H3K4 has been determined by the laboratory of Dinshaw
Patel (Memorial Sloan-Kettering Cancer Center, New York, NY, USA) in
collaboration with David Allis. Interestingly, this structure provides an
immediate explanation of why NURF-301 specifically reads H3K4 trimethylation
but not the trimethylated states of H3K9 or H3K27, which are read,
respectively, by the HP1 and Polycomb (PC) chromodomain proteins
(Fischle et al., 2003). This
specific reading depends on the simultaneous binding by NURF-301 to the lysine
in position 4 and to the arginine in position 2 of the N-terminal tail of
histone H3, with the additional requirement of a threonine residue in between
these two amino acids (no threonine is present between H3K9 and H3K27). These
data provide a model to explain the epigenetic maintenance of active
chromatin, during which MLL and WDR5 collaborate to produce the efficient
trimethylation of H3K4. This trimethylation mark is then recognized by the
NURF complex, which remodels the nucleosomes to open chromatin structure at
trxG target genes (C. D. Allis and D. J. Patel, personal communication).
Another way of interpreting active histone marks to drive transcription was
highlighted by Steven Henikoff (Fred Hutchinson Cancer Research Center,
Seattle, WA, USA). Histones come in different `flavours' –predominant
isoforms and histone variants. Histone H3.3 differs from H3 by only four amino
acids, but its biology is very different from that of H3. H3.3 marks active
chromatin, and it can be deposited on chromatin in a replication-independent
manner (Ahmad and Henikoff,
2002). Recently, genome-wide mapping of H3.3 indicated that
histone H3 replacement occurs predominantly at sites abundant in RNA
polymerase II and methylated H3K4. In addition to H3 replacement, the
promoters of active genes undergo a more radical chromatin transition in which
histones are stripped from the DNA template
(Mito et al., 2005). Moreover,
histone H3.3 was found to be enriched on genes located in the hyperactive
Drosophila male X-chromosome compared with autosomal genes,
suggesting that this histone variant might enhance the processivity of RNA
polymerase (Mito et al.,
2005). Thus, histones can either be modified or removed, perhaps
not exclusively, in order to activate transcription.
Chromatin transitions can be dynamically regulated during development. One
provocative example of such dynamics was given by Jeannie Lee (Howard Hughes
Medical Institute, Massachusetts General Hospital, Boston, MA, USA), who
studies mechanisms of mammalian X-chromosome inactivation (XCI). In XCI, one
of the two female X chromosomes is silenced, which equalizes the dose of
X-linked gene products in X/X females and X/Y males
(Heard, 2005;
Huynh and Lee, 2005;
Reik and Lewis, 2005).
X-chromosome silencing is achieved by upregulating the expression of the
Xist noncoding transcript, which then spreads in cis on the future
inactive X chromosome and induces multiple repressive chromatin modifications
that turn off most of the X-linked genes. The Lee laboratory has shown that
Xist is activated transcriptionally at the onset of XCI. Its
transcriptional regulation is mediated by Tsix, the antisense partner
of Xist. On the future active X chromosome, persistent Tsix
transcription, a `euchromatic character', paradoxically represses
Xist transcription. Tsix transcription recruits or activates
the DNA methyltransferase Dnmt3a, which, in turn, methylates CpG dinucleotides
on the linked Xist allele and stably represses that allele.
|
). This
`heterochromatic character' is a paradoxical, but not an unprecedented,
condition for an active locus, as some genes can stay active in a
heterochromatin environment (Yasuhara et
al., 2005). However, in the case of Xist this state is
reversed in the maintenance phase of XCI; that is, H3K27 becomes
hypomethylated, H3K4 becomes hyperdimethylated and H4 becomes hyperacetylated
(Sun et al., 2006). Thus, we
now know the series of chromatin modifications that pre-empts and determines
XCI (see Fig. 1). A future
challenge will be to understand how a transient heterochromatin state can
result in Xist activation, and how the mark is then reversed to the `normal'
situation during later stages. Higher-order chromatin organization and nuclear architecture
Within the cell nucleus, chromatin is not folded in a string of
nucleosomes. Depending on the degree of condensation of specific loci,
nucleosome fibres can fold further to form the so-called 30 nm chromatin fibre
and higher-order chromatin structures, the architecture of which is
essentially unknown. These higher-order structures offer possibilities for
regulating chromatin domains, as was illustrated by Peter Fraser (The Babraham
Institute, Cambridge, UK). The Fraser laboratory has shown previously that
multiple genes distributed along the arm of chromosome 7, which contains the
ß-globin locus, can cluster in a so-called transcription factory with the
active ß-globin domain, when transcribed in erythroid cell progenitors
(Osborne et al., 2004). They
have now extended this analysis to the study of many loci from different
chromosomes. Interestingly, several genes were found to colocalize in
transcription factories at high frequencies, suggesting preferential
arrangements of specific subsets of genes or networks. In addition to
colocalization detected in FISH assays, long-distance interactions were also
detected using the chromosome conformation capture (3C) assay
(Dekker et al., 2002),
suggesting that these interactions might involve molecular contacts among the
interacting partners. Further analysis showed that the interchromosomal
colocalizations depend, in part, on the preferred neighbour arrangement that
some chromosomes have in this specific cell type. However, colocalization is
also dynamically regulated as a function of the transcriptional state of the
genes and, importantly, transitions from a non colocalized inactive state to a
colocalized active state can be rapid (P. Fraser, personal communication).
This suggests that, rather than being a passive component in the nucleus, the
transcription machinery can represent a potent engine that is able to shape
cell nuclear architecture.
On the other side of the coin, silencing machines can also generate
long-distance interchromosomal association. This phenomenon was discussed by
Giacomo Cavalli (Institute of Human Genetics, CNRS, Montpellier, France), who
is studying PcG-mediated silencing in Drosophila. PcG proteins
silence their target genes via binding to regulatory regions called PcG
response elements or PREs. In addition to regulating the closest gene promoter
in cis, these elements can also act in trans, as PcG-mediated silencing is
often enhanced in the presence of multiple PRE copies
(Kassis, 2002). PRE-containing
elements, such as the Fab7 or the Mcp regulatory regions
from the Drosophila Hox locus called the Bithorax complex, can pair
in the nucleus even when located on different chromosomes
(Bantignies et al., 2003;
Vazquez et al., 2006).
Components of the RNA interference (RNAi) gene silencing machinery have now
been shown to colocalize with nuclear compartments with high concentration of
PcG proteins (called PcG bodies) (Fig.
2) and to contribute to the maintenance of long-range nuclear
interactions among PcG target elements
(Grimaud et al., 2006). As
RNAi components have previously been shown to mediate telomere clustering in
S. pombe (Hall et al.,
2003), one way in which the RNAi machinery might induce chromatin
silencing could involve an evolutionarily conserved function in the regulation
of nuclear architecture.
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The correct deployment of developmental programmes requires both the
capacity to progress dynamically through a series of intermediate states,
involving the reprogramming of cell fates and the plasticity of cell-cell
interactions, and the maintenance of homeostasis (i.e. of a stable response to
variable environmental conditions). Several presentations discussed how
epigenetic components might contribute towards reaching the best compromise
between plasticity and stability during development. PcG proteins are best
known for their ability to stably maintain the regulatory states of Hox genes
during development. However, the function of these factors can be transiently
downregulated by the JNK pathway during tissue injury, as shown by work
presented by Renato Paro (Centre for Molecular Biology, University of
Heidelberg, Germany). This dynamic response might be crucial to the
reprogramming of cell fates, in order to allow cells close to the site of
injury to proliferate and to acquire new fates, thus regenerating the complex
patterns of the tissue prior to injury
(Lee et al., 2005).
The dynamic regulation of PcG proteins occurs not only in flies, but also
in plants and in vertebrates. Ueli Grossniklaus (University of Zürich,
Zürich, Switzerland) described the complex and dynamic regulation of the
MEDEA (MEA) locus in Arabidopsis. MEA encodes a
homologue of the PcG protein Enhancer of Zeste [E(Z)], the PcG H3K27-specific
histone methyltransferase. He showed that MEA is able to autoregulate its own
promoter in a dynamic parent-of-origin-specific manner: the initial
downregulation of the maternal allele around fertilization depends on MEA but
not on other components of the PRC2-like complex, while the later repressive
effect on the paternal allele requires all members of the complex
(Baroux et al., 2006).
In vertebrates, PcG factors are not only involved in the maintenance of
differentiated cells but also of cellular totipotency
(Lessard and Sauvageau, 2003;
Gil et al., 2004). Rudolf
Jaenisch (Whitehead Institute for Biomedical Research and Massachussets
Institute of Technology, Cambridge, MA, USA) discussed the implications of the
genome-wide mapping of the chromosomal distribution of PcG proteins in human
and mouse embryonic stem (ES) cells. This was achieved through a combination
of chromatin immunoprecipitation with hybridization on DNA microarrays (ChIP
on chip) in collaboration with the laboratory of Richard Young (Whitehead
Institute for Biomedical Research and Massachussets Institute of Technology,
Cambridge, MA, USA). Their data indicate that PcG proteins maintain ES cell
identity by simultaneously repressing a number of developmental transcription
factor genes (Fig. 3).
Repression correlates with the trimethylation of histone H3K27 and the
exclusion of RNA polymerase II from most target genes. Importantly, ES cell
differentiation activates the expression of these genes, which occurs
concomitantly with the loss of PcG proteins from their regulatory regions
(Boyer et al., 2006;
Lee et al., 2006). Many of the
PcG target genes have previously been shown to be bound by the key
transcription factors OCT4, NANOG and SOX2
(Boyer et al., 2005;
Loh et al., 2006). This raises
the possibility that PcG proteins act as repressors of gene transcription by
collaborating with these pluripotency transcription factors to maintain stem
cell identity, as well as allowing the reprogramming of stem cell fate by the
appropriate differentiation stimuli.
It remains to be seen whether PcG proteins repress their target genes via dedicated DNA elements analogous to Drosophila PREs. This is a long-standing issue and no mammalian PREs have been identified to date, but Keji Zhao (NHLBI, NIH, Bethesda, MD, USA) presented his group's studies of human chromosomal regions that are characterized by high levels of histone H3K27 trimethylation. Several of these sites are bound by PcG proteins and drive gene silencing when tested in functional assays (K. Zhao, personal communication), suggesting that they might represent interesting candidates for human PREs.
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).
Remarkably, the distribution of PcG proteins in large domains, sometimes many
tens of kilobases in size, their tendency to regulate genes that encode
transcription factors, and some of the regulatory pathways targeted by these
proteins are conserved between mammals and flies. Moreover, an independent
ChIP on chip study of the developmental profile of PcG protein distribution in
Drosophila shows that, similar to vertebrates, PcG proteins associate
dynamically with several of their target genes during development
(Nègre et al., 2006).
This evolutionary conservation suggests that PcG proteins play a pivotal role
in driving and maintaining cell fates, maintaining cellular memory and, when
necessary, allowing for plasticity of cell fates.
Epigenetic regulation can thus shape developmental landscapes, providing
developmental robustness at the same time as allowing adjustment to variable
environmental conditions. However, damage to or perturbation of epigenetic
components can also result in disease, such as various genetic syndromes or
cancer. Stephen Baylin (Johns Hopkins University, Baltimore, MD, USA)
discussed cancers that are caused by the hypermethylation, but not the
mutation, of the HIC1 gene DNA. It is known that HIC1
normally exerts its tumour suppressor function in cooperation with
P53 (TP53 – Human Gene Nomenclature Database).
HIC1 encodes a transcriptional repressor that requires two protein
domains. The Baylin laboratory showed that one of these, the POZ domain, is
able to interact with the NAD-dependent SIRT1 histone deacetylase and,
together, they repress the SIRT1 promoter. The same complex also deacetylates
P53, blocking its proapoptotic activity in response to DNA damage
(Chen et al., 2005). During the
course of aging, HIC1 is normally hypermethylated. This event might
promote P53 inactivation via upregulation of SIRT1, and this might, in turn,
increase the survival of aging cells and their consequent exposure to DNA
damage. However, an excessive drift towards the chronic repression of
HIC1 might also increase the risk of neoplastic transformation. This
highlights the fact that these processes can be beneficial for health, on one
hand, yet they represent intrinsic risk factors for some diseases, on the
other (Feinberg et al.,
2006).
Inheritance of epigenetic states
Another case of epigenetically derived cancer involves an intriguing
phenomenon – genomic imprinting – in which only a single allele
(either the paternally or the maternally inherited one, depending on the gene
locus) is expressed, while the other allele is repressed, a process that
mostly involves DNA methylation (Delaval
and Feil, 2004). Laurie Jackson-Grusby (Children's Hospital Boston
and Harvard Medical School, Boston, MA, USA) discussed an elegant genetic
study, performed in Rudolf Jaenisch's laboratory, that involves the
consecutive use of Cre and flp recombinases to generate a transient knockout
of the DNA methyltransferase gene, Dnmt1, in mouse ES cells. In cells
that experience a transient loss of DNMT1 function, global levels of DNA
methylation are preserved, while imprinted genes lose their DNA methylation
and their parent-of-origin-specific silencing. Embryonic fibroblasts derived
from ES cells that have lost imprinted gene expression in this way showed
increased growth rate, spontaneous immortalization and the ability to induce
cellular transformation that correlates with reduced levels of P19 and P53.
Finally, chimeric animals derived from imprint-free ES cells developed
multiple tumours (Holm et al.,
2005). This demonstrates that the transient loss of a DNA
methyltransferase is sufficient to induce heritable loss of imprinting, which
can predispose cells to increased risk of neoplastic transformation.
Emma Whitelaw (Queensland Institute of Medical Research, Brisbane,
Australia) presented an extreme case of epigenetic inheritance that can be
transmitted to subsequent generations in mice. This involves the agouti
viable yellow (Avy) allele of the agouti coat colour locus.
Isogenic Avy mice display variable expressivity, with coat shades
from full yellow, through variegated yellow/agouti, to full agouti
(pseudoagouti). Previous work from the Whitelaw laboratory has shown that the
expressivity of the agouti phenotype depends on the phenotype of the dam:
agouti dams produce offspring with a higher proportion of agouti phenotypes
(Morgan et al., 1999). This
phenomenon of transgenerational inheritance of chromatin states is present in
fungi and in other animal species (Grewal
and Klar, 1996; Cavalli and
Paro, 1998), and is relatively widespread in plants
(Takeda and Paszkowski, 2006).
Recently, the Whitelaw laboratory carried out an ENU mutagenesis screen for
modifiers of position effect variegation using a GFP transgene. They isolated
several mutants that both suppressed or enhanced variegation. Interestingly,
in most cases, these modifiers also affect the Avy phenotype, with
parent-of-origin- and sex-specific effects
(Blewitt et al., 2005). This
screen might thus prove to be useful for the isolation of mouse genes that are
involved in heterochromatin formation and gene silencing. In addition, it
seems also to indicate that parent-of-origin-specific effects, and perhaps
also transgenerational epigenetic inheritance, might be more widespread in
mammals than was previously thought.
Conclusion
The findings presented at this meeting, including the presentations discussed here, together with others that I could not discuss owing to space constraints, show how much epigenetic regulation is intimately linked to developmental processes. Epigenetic factors can both stabilize development by buffering environmental variation, as well as guide the organism through remodelling events that require plasticity of cell fate regulation. Ongoing research will help to clarify how these apparently opposing functions are coordinated, and it is likely to unravel novel molecular mechanisms involved in this regulation. The future is with epigenetics.
ACKNOWLEDGMENTS
I thank the organizers for this fantastic meeting, which included the presentation of a number of exciting new findings, many possibilities for informal interactions among participants and, on top of it, great snow! I also thank Frédéric Bantignies, Charlotte Grimaud, Rudolf Jaenisch and Jeannie Lee for critically reading the manuscript and generously providing figures. I thank all participants who have allowed their unpublished data to be discussed. I apologize to many colleagues whose excellent work I could not discuss here owing to lack of space.
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