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Friday June 4/Evening
POSITION EFFECTS & NUCLEAR ORGANIZATION
Derek Goto
The
session this evening was preceded by the ‘Reginald G. Harris
Lecture’ presented by Gary Felsenfeld (NIH).
Bruce Stillman (CSHL) introduced Felsenfeld and explained the
history behind the annual CSHL Symposia and associated traditions, such
as the Reginald G. Harris Lecture that is given by a scientist who has
played a major role in the field.
One of Felsenfeld’s important contributions has been the
identification of boundary elements and this was the focus of his
lecture.
Gary Felsenfeld began with an explanation of the two functions of
boundary elements: to provide a barrier against the spread of condensed
chromatin onto active genes, and to prevent adjacent genes from
interacting with each other by blocking enhancers.
This was followed by an overview of his work that led to the
identification of boundary elements in the chicken beta-globin locus and
purification of CTCF as the protein binding these elements.
The subsequent discovery that CTCF interacts with nucleophosmin
to tether the boundary elements to fixed regions in the nucleus revealed
the mechanisms behind their function as insulators.
Identification of several addition regions within the boundary
elements that are required for the barrier function were then described.
After presenting a series of data profiling various epigenetic
histone modifications, Felsenfeld provided a model for the mechanism by
which boundary elements act as barriers.
Recruitment of regulatory factors by multiple regions results in
the creation of local epigenetic modifications at the boundary element
site, which interferes with the mechanisms for spreading of condensed
chromatin from neighbouring regions.
The
session on ‘Position effects and nuclear organisation’ followed the
Reginal G. Harris Lecture and was chaired by Genevieve Almouzni (Institut
Curie Recherche, France).
The first talk was presented by Daniel Gottschling (Fred
Hutchinson Cancer Research Center).
He had originally planned to give a talk on the relationship
between histone ubiquitin marks and telomeric silencing but got up and
announced that he was going to talk about something completely
different.
Nevertheless, Gottschling gave an exciting talk on work in his
lab by Michael McMurray looking at age-induced gene instability that
generated much discussion afterwards.
Based on an interest in studying the correlation between age and
cancer, they had chosen to investigate the influence on age on genomic
instability using Saccharomyces cerevisiae.
Gottschling described a screen they had established in which
several recessive heterozygous markers were introduced into yeast
allowing loss of heterozygosity (LOH) to be monitored.
The life span of yeast is defined by the number of daughter cells
produced by the mother cells, which normally numbers 30.
Following each division, they had separated each daughter cell in
sequential order and allowed it to form a colony.
What they found was that after approximately 25 cell divisions by
the mother, daughter cells began to show an amazing loss of genomic
instability.
This was due to LOH through non-reciprocal recombination that
only occurred in the daughter cells and never in the mother cells.
Moreover, the switch to LOH appeared to be on its own clock as
extending the ‘life-span’ of the mother cells from 30 to 50
divisions had no effect on the age at which genomic instability appeared
in the daughter cells.
As something for the audience to think about (and to generate
discussion in the bar afterwards), Gottschling made an interesting
comparison with stem cells: the mothers may be like stem cells that must
retain genomic integrity and so any instability is passed to the
daughters as may be expected for differentiated cells.
In the last few minutes of the talk possible mechanisms for this
were discussed.
Gottschling finished by presenting evidence supporting a
hypothesis that LOH in daughters from older mothers is due to
accumulation of damaged proteins in ageing mothers that is inherited by
the progeny.
Another
interesting talk was provided by Susan Gasser (University of Geneva) who
is looking at the relationship between 3D architecture in the nucleus
and epigenetic mechanisms in S. cerevisiae.
This featured a number of 3D images and movies in which CFP and
GFP markers had been used to imaging telomere clustering and movement at
the nuclear periphery.
Despite the anchoring of centromeres, telomeres were shown to be
display dynamic movement but always back and forth along the nuclear
periphery.
Dynamic movement of tagged euchromatic regions was also shown,
which was always within a defined domain within the nucleus.
Interestingly, telomere clustering and movement was dependent on
the chromosome: the two ends of some chromosomes were always clustered
and moving together, whereas the ends of other chromosomes moved
separately.
The talk followed a logical progression on aspects of chromosome
movement, leading to evidence for the existence of two independent
mechanisms for anchoring the telomeres to the nuclear periphery.
Wendy
Bickmore (MRC Human Genetics Unit) followed Gasser with a talk on how
higher order chromatin structure and nuclear organization is modulated
to control developmental regulation of the HoxB locus in mice.
The last talk of this informative session was given by Steven
Henikoff (Fred Hutchinson Cancer Research Center) who discussed how
histone variants specify modes of chromatin assembly.
Henikoff presented their recent data showing that
replication-independent replacement of histone H3 with H3.3 provides a
mechanism for resetting silent chromatin modifications and maintaining a
transcriptionally active state.
One of interesting points from Henikoff talk was the suggestion
that non-dividing cells continue to replace H3 with H3.3 in the absence
of replication, leading to a statement well received by the audience:
All our brains are probably H3.3 brains!!
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) |
Derek Goto
(Martienssen lab)
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