Program & Abstract Book - EPFL Latsis Symposium 2009

EPFL Latsis Symposium 2009: Understanding Violence
P-27
Depicting t h e r o l e o f t h e kap1
e p i g e n e t i c r e g u l a t o r in b e h a v i o u r a l
v u l n e r a b i l i t y t o s t r e s s
Marquis, Julien 1 ; Jakobsson, Johan 2 ; Bisaz, Reto 1 ; Sandi,
Carmen 1 ; Trono, Didier 1
Poster Abstracts
1 Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland;
2 Faculty of medicine, Lund university, 22184 Lund, Sweden
Growing evidence points to the role of epigenetics in translating environmental
stimuli into long-lasting changes of gene expression in the brain.
Contrasting with the abundance of data pointing to the key role of epigenetics
in animal behaviour, relatively little is known about the molecular
mediators of this process. As part of a broad effort to define the roles of
the KRAB/KAP1 gene regulation pathways in vivo, we carried out a reverse
genetic approach by generating a mouse model in which the KAP1 gene
was specifically inactivated in neurons of the adult forebrain. Behavioral
studies reveal heightened level of anxiety-like and exploratory activity in
these mice, as well as stress-induced alterations in spatial learning and
memory (Jacobsson et al., Neuron, 2008, 60, 818-31). At the molecular
level, transcriptome analyses detect the dysregulation of a small number
of genes correlated with a decrease of H3K9-me3 and an increase of
H4Ac, consistent with KAP1-dependent chromatin changes.
Our initial molecular studies were performed on whole hippocampus, that
is, on a mixture of KAP1-negative and KAP1-positive cells. We are now
using laser-dissection to recover selectively KAP1-deleted cells and also
analyze separately different hippocampal sub-area. We anticipate that,
associated with transcriptome and chromatin analyses, the method should
generate robust data to help deciphering the cascade of molecular event
linking KAP1 to the observed “stress phenotype”.
The Cre mediated hippocampal-KAP1 deletion occurs at approximately
15-30 days of age, that is, when murine macroscopic brain structures are
fully developed. Nevertheless, we cannot rule out that KAP1 deletion does
not primarily impact on immature, developing neurological networks. To
address this point, we have generated a similar mouse model but expressing
a tamoxifen-inducible form of Cre. We will now study whether inducing
KAP1 deletion at different ages has an impact on the “stress behaviour”.
Along the same line, we will study the reversibility of that phenotype by
controlling the re-expression of KAP1 through doxycycline treatment of
animals carrying an rtTA-regulated expression system.
Work performed in our laboratory indicates that KAP1 is an important mediator
of stem cell proliferation/differentiation. Interestingly, several observations
support the hypothesis that depression could be correlated with
an altered adult neurogenesis in the hippocampus. Therefore, through
combined labelling with BrdU and several neuronal differentiation marker,
we are testing the possibility that adult neuronal maturation could be affected
in hippocampal KAP1-deleted animals. The results of this analysis
may provide insight into the biology of depression.
81