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Monday June 7/Afternoon
EPIGENETICS & DISEASE
Michael Ronemus
Perturbations in the
action of epigenetic mechanisms can have severe consequences for an
organism’s well-being. Still, only recently have we begun to understand
how epigenetic defects can underlie disease in humans. Mutations in the
methylcytosine-binding protein MeCP2 cause Rett Syndrome, a disorder of
X-linked mental retardation that affects 1 in 10,000 women. Another
common disorder of mental retardation, Prader-Willi syndrome, results
from disruptions in genomic imprinting on chromosome 15. And whereas the
ultimate relationship between epigenetics and cancer remains to be
elucidated, it is clear that a multitude of epigenetic aberrations are
associated with many cancers.
Given this level of
interest, it’s no surprise that the links between epigenetics and
disease have been one of the most active areas of research in
epigenetics. But even while these connections are being made,
understanding of the epigenetic mechanisms themselves is being further
refined. In this spirit, the Epigenetics and Disease session was focused
with one eye on the fundamental mechanisms, and the other on what
happens when epigenetics has gone awry.
One of the most active
areas in current epigenetics research is delineating the full spectrum
of covalent modifications to histone tails and how they contribute to a
variety of cellular processes. Steve Saunders, of Tony Kouzarides’s lab
(University of Cambridge, UK) detailed work in the yeast S. pombe
on methylation of the lysine-20 residue of histone H4 (H4-K20).
Methylation of H4-K20 is carried out by the Set9 histone
methyltransferase. Unlike many other modifications of histone tails,
methylation of H4-K20 is neither associated with heterochromatinization
nor gene expression. Although there is some localization of H4-K20 with
specific chromosomal regions, the real clue as to what Set9 may be doing
is provided by the mutant phenotype: set9 cells are
hypersensitive to DNA damage. But how Set9 acts in the DNA damage
response is unclear, as a number of pathways—including non-homologous
end joining, double-strand break repair and homologous recombination—are
unaffected in the set9 background.
A presentation by
Yoshihiro Nakatani (of the Dana-Farber Cancer Institute and Harvard
Medical School) addressed a fundamental issue concerning the histone
code: how is histone-encoded epigenetic information reliably maintained
after DNA replication? To address this question, Nakatani and colleagues
affinity-tagged histone H3.1 and purified the DNA synthesis-dependent
H3.1 complex. Present were the chaperones CAF-1 and ASF1, NASP (which
binds the H1 linker), the histone acetyltransferase HAT1 and importin-4.
But instead of an H3-H4 tetramer—the full complement per complete
histone—they found what appeared to be a dimer. Nakatani interpreted
this as possible support for a semi-conservative model of histone
duplication, in which each tetramer is split into two dimers following
DNA replication. A new dimer then binds to each of the daughter strands,
maintaining all modifications in a ‘hemi’ state until the tetramer is
restored by the addition of another dimer. Nevertheless, this remains to
be fully reconciled with existing data.
In a more broadly based
talk, Maarten van Lohuizen (of the Netherlands Cancer Institute)
discussed the roles of mammalian PcG (polycomb group) complexes in
development and cancer. PRC1 and PRC2 (Polycomb repressive
complex) are linked to inactivation of the X chromosome. PRC1
interacts with the histone variant macroH2A as well as the E3 ubiquitin
ligase SPOP, and it localizes to the inactive X chromosome in a cell
cycle-dependent fashion. When the expression of these PRC1-related
components is inhibited, X inactivation is lost. In the second portion
of his talk, van Lohuizen focused on the specific functions of Bmi1, a
PcG factor that interacts with PRC1 and was originally characterized as
an oncogene. Bmi1 is thought to be coupled to cell differentiation and
proliferation, and its inhibition in the mouse results in progressive
neurological abnormalities. Overexpression of Bmi1 is correlated with
active, aberrant signaling in the Sonic hedgehog (Shh) pathway—a key
contributing factor to medulloblastoma onset, and an indication that
Bmi1acts to control neuronal stem cell renewal. Based on these and other
data, van Lohuizen concluded that the heritable silencing mediated by
PcG complexes such as PRC1 and PRC2 is required to maintain
differentiated cell fate in diverse developmental contexts.
The genetic (and
epigenetic) basis of psychiatric disorders is, at best, poorly
understood. Amar Klar (of the National Cancer Institute, US) discussed
recent progress his lab has made in determining how altered segregation
of ‘epialleles’—which do not differ in DNA sequence but have been
heritably silenced—may contribute to psychoses. Taking cues from his
early work on mating type switching in S. pombe, Klar explained
how such asymmetric inheritance during early cell divisions accounts for
the production of two functionally non-equivalent hemispheres in the
normal human brain. But what if this imprint is altered? Klar pointed
out that individuals diagnosed as psychotic are three times as likely to
be left-handed as the population at large, suggesting that disruption of
normal asymmetric inheritance early in development might lead to mental
disease. In support of this notion, several families in the published
literature with independent chromosome 11 translocations show a 50%
incidence of mental disorder that cosegregates with the translocation.
No genes are shared between the independent translocation, however,
indicating that any linked effect must be acting at a different
level—for which epigenetic alterations represent an attractive
candidate.
Other
Dispatches
Symposium
69 Live
Symposia
Past (a bit of history and photographs from previous Symposia)
Online
Symposium Volumes (searchable database of past Symposia volumes and
currently received manuscripts) |
Michael Ronemus
(Martienssen lab)
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