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The intracellular signaling mechanisms mediating OR-dependent
gene silencing remain largely unknown, however. In this
presentation I will discuss recent experiments focusing on the
genetic and epigenetic mechanisms subserving OR gene silencing.
Acknowledgements: This work was supported by a grant from the
NIDCD (R01 DC02253).
#11
PRESIDENTIAL SYMPOSIUM:
NEURAL EPIGENETICS & OLFACTION
Epigenetic Regulation of Olfactory Receptor Expression
Stavros Lomvardas
UCSF/Anatomy San Francisco, CA, USA
Olfactory receptor gene choice, the process of the stochastic
activation of one out of a thousand alleles is poorly understood.
Our data are consistent with an epigenetic control of olfactory
receptor expression. Our experiments suggest that that in the mouse
olfactory epithelium, olfactory receptor (OR) genes are marked, in
a highly dynamic fashion, with the molecular landmarks of
constitutive heterochromatin. The cell-type and differentiation
dependent deposition of H3K9me3 and H4K20me3 along the OR
clusters is, reversed during the process of OR choice for monogenic
and mono-allelic expression. Our findings provide genetic and
biochemical evidence that demethylation of the silenced OR alleles
is necessary for olfactory receptor activation and for the subsequent
terminal differentiation of the olfactory neuron. Moreover, we
provide evidence for a spatial regulatory layer in OR choice.
Using a complex DNA FISH probe and super-resolution imaging
technologies we demonstrate that the active OR allele is spatially
separated from the aggregated silenced ORs. Genetic manipulation
of the spatial segregation of active and inactive alleles results in
dramatic changes in olfactory receptor expression and violation of
the “one receptor per neuron rule”. Acknowledgements: R03
DC010273 Epigenetic Regulation of Olfactory Receptor
Expression
#12
PRESIDENTIAL SYMPOSIUM:
NEURAL EPIGENETICS & OLFACTION
Coding olfaction
Peter Mombaerts
Max Planck Institute of Biophysics Frankfurt, Germany
Each olfactory sensory neuron (OSN) in mouse chooses one of
1,200 odorant receptor (OR) genes for expression. OR genes are
chosen for expression by greatly varying numbers of OSNs.
The mechanisms that regulate the probability of OR gene choice
remain unclear. Here, we have applied the NanoString platform of
fluorescent barcodes and digital readout to measure RNA levels of
577 OR genes in a single reaction, with probes designed against
coding sequences. In an inbred mouse strain with a targeted
deletion in the P element, we find that this element regulates
OR gene choice differentially across its cluster of 24 OR genes.
Importantly, the fold changes of NanoString counts in ΔP or ΔH
mice are in very close agreement with the fold changes of cell
counts, determined by in situ hybridization. Thus, the P and H
elements regulate the probability of OR gene choice, not OR
transcript level per OSN.
#13
PRESIDENTIAL SYMPOSIUM:
NEURAL EPIGENETICS & OLFACTION
Epigenetic Gene Regulation in Neurodegeneration and Repair
Johannes Gräff, Li-Huei Tsai
Picower Institute for Learning and Memory, Department of Brain
and Cognitive Sciences, Howard Hughes Medical Institute,
Massachusetts Institute of Technology Cambridge, MA, USA
Chromatin modifications, particularly histone-tail acetylation,
have recently been implicated in memory formation. Increases in
histone-tail acetylation that are induced by inhibitors of histone
deacetylases (HDACis) facilitate learning and memory in
wildtype mice as well as in mouse models of Alzheimer’s-like
neurodegeneration. Moreover, increases in histone acetylation by
HDACi treatment induce dendritic sprouting and increase synapse
numbers. Long-lasting remodeling of neural circuits, therefore,
may underlie the beneficial effects of HDACis on cognition.
Through a combination of genetic and pharmacological
approaches, we have identified histone deacetylase 2 (HDAC2) to
be a major HDAC involved in regulating the expression of genes
essential for synaptic plasticity and memory formation. HDAC2-
deficient mice exhibit facilitated long-term potentiation (LTP),
whereas HDAC2 overexpressing mice exhibit impaired learning
and hippocampal LTP. Moreover, HDAC2-deficient mice are
refractory to the beneficial effects of HDACis in enhancing
cognition. Recently, we found that HDAC2 is dysregulated in
mouse models of Alzheimer’s disease as well as in Alzheimer’s
disease human postmortem brains. We propose a model whereby
HDAC2 dysregulation causes an epigenetic blockade of gene
expression that contributes to cognitive impairment in
neurodegenerative diseases such as Alzheimer’s. These
observations suggest that targeting chromatin remodeling may
serve as a new avenue for treating cognitive decline caused
by neurodegeneration.
#13.5
PLATFORM PRESENTATIONS:
OLFACTION
Baleen Whales and Tubenose Seabirds —A Colossal
Chemosensory Convergence?
Julie C. Hagelin
1
, Janice M. Straley
2
, Lindsey B. Nielson
3
,
Andy Szabo
4
1
University of Alaska Fairbanks, Institute of Arctic Biology
Fairbanks, AK, USA,
2
University of Alaska Southeast Sitka, AK,
USA,
3
College of the Atlantic Bar Harbor, ME, USA,
4
University of Alaska Southeast Juneau, AK, USA
How filter-feeding baleen whales locate ephemeral swarms of
zooplankton prey remains a biological mystery. Though it is widely
believed that all whales cannot smell, evidence points to the
contrary, including indigenous knowledge, anatomical and genetic
data. Baleen whales face a foraging “problem” that is similar to
tubenose seabirds (e.g. petrels, shearwaters). Below we address the
parallels and present initial data for whales. Classic seabird studies
revealed that tubenoses use olfactory-mediated foraging, in which
they oriented into the wind upon approaching experimental
“plumes” of food scent. More recent work has discovered avian
attraction to dimethyl sulfide (DMS), a reliable indicator of
zooplankton prey. We observed humpback whales (
Megaptera
novaeangliae
) in southeast Alaska for evidence of behaviors
consistent with the use of odor cues. Our data suggest that whales
orient into the wind (n = 231, df = 1,
X
2
=54.6, P <0.0001). This
suggests that humpbacks are well positioned to perceive volatile
O R A L A B S T R A C T S