Tip60 HAT Action in Environmental Enrichment Induced Cognitive Restoration
Songjun Xu, Eric Koza, Iqbal Sahira, Melissa Mabasa and Felice Elefant
Department of Biology, Drexel University, Philadelphia PA 19104
Tip60 is required for normal mushroom body
structure
Pirooznia & Elefant, 2013
One of the best characterized
epigenetic modifications crucial
for learning and memory is
histone acetylation, that regulates
cognitive gene expression by
controlling chromatin packaging
in neurons.
Yet despite the
central importance of histone
acetylation in higher order brain
function, the select histone
acetyltransferases (HATs) that
generate cognition linked
epigenetic signatures in the brain,
and their mechanisms of action
remain largely unknown.
One promising candidate is Tip60, a HAT shown by our laboratory to play a
critical role in regulating neuronal genes linked to neurodevelopment and
cognition.
A
B
α'
C
α
α/α’
α/α’
γ
β’
β/β’
β
D
1400
Area
measurement
(Arbitrary Unit)
Disruption of epigenetic gene control mechanisms in the brain causes significant
cognitive impairment that is a debilitating hallmark of most aging associated
neurodegenerative disorders including Alzheimer’s disease (AD).
Adult brain
Introduction
Tip60 HAT action is required to induce a
neuroadaptative transcriptional response to EE
α/β lobes
TIP60 HAT MUT
E KC
γ lobe
α’/β’ lobes
β/β’
1200
Learning&
or&
memory&
1000
800
600
400
**
*
calyx
Tip60 +GFP
Merge
**
200
0
Control
dTip60E431Q dTip60WT
Circadian&rhythm
Nucleo;de&binding
Select&115&EE&
unresponsive&genes&
in&Tip60&HAT&MUT&
for&func;onal&
analysis&
Phosphoryla;on
Neuron&&
Development
Tip60 HAT activity promotes axonal outgrowth in mushroom body (MB). Adult
MB tagged and visualized with mCD8-GFP driven by pan-MB driver, OK107-GAL4. (A) GFP labeling
shows stereotypic pattern of γ and α/β lobes in control MB. (B) Tip60 HAT mutant flies display severe
reduction in length and width of α and β lobes (arrows). (C) dTip60WT has no effect on MB morphology.
(D) Quantification of lobe area (n=20); p ≤ 0.05; **p ≤ 0.001. (E) Tip60 expression in MB neuronal
Kenyon cell (KC) nuclei with halo of GFP expression in the cell membrane and calyx (dendritic
processes).
EE unresponsive genes in Tip60 HAT mutant are enriched for learning and memory function
Q
31
E4
ISO
$d T
0$
ip6
EE
$dT
E
0$
6
p
i
1Q
43
IS
T
W
O$
E
T
E$W
EE unresponsive genes in Tip60 HAT mutant are
enriched for learning and memory function
0thers*
Sensory* 5%*
percep=on*
7%*
Environmental Enrichment (EE) promotes neuronal
branching and cognitive restoration
Olfactory*
learning*and*
memory*
21%*
Metal*ion*
binding*
7%*
Reproduc=ve*
process*
development*
8%*
BTB/POZ*
domain*
15%*
Iron*ion*binding*
11%*
Signaling*
14%*
Pep=dase*
ac=vity*
12%*
Tip60 rescues impaired EE neuroadaptative transcriptional response in
the AD neurodegenerative fly brain
Bushey et al., 2011
EE response
2.5"
EE increases histone acetylation levels in mice hippocampus
Fold%Change
2"
EE"expression"
larger"than"ISO"for"
every"gene
EE induced
EE"always"promote"
upregulation
neuronal"gene"up1
inregula2on
WT flies
Overexpressed"Tip60"
rescued in AD
always"rescues"APP"
flies
with excess
induced"neuronal"
gene"misregula2on
Tip60
APP"always"down"
regulated"rela;ve"
EE response
to"WT APP"always"induces"
down1regula2on"on"
dampened
in
neuronal"func2on"
AD
flies
genes"
1.5"
1"
0.5"
**
**
*
** **
0"
obp99%
* **
Pka)R1%
*
**
mbm%
**
**
*
**
**
fru%
** **
jing%
**
P%
Selected%Genes%from%Microarray%assay
ISO%WT%
EE%WT%
ISO%APP%
EE%APP%
ISO%APP;dTip60WT% EE%APP;dTip60WT%
Zhu et al., 2007
Van Praag et al., Nature Neuroscience, 2000 Fischer et al, 2007
Tip60 has been implicated in the age-related neurodegenerative disorder
Alzheimer’s disease (AD) via its interaction with the AD linked amyloid
precursor protein (APP) C-terminus intracellular domain (AICD).
Tip60 HAT action is required for a beneficial
neuroadaptive response to EE
Environmental
Conditions
W1118
Non-amyloidogenic processing
Appropriate levels of Tip60
HAT activity are required
for EE mediated
neuroadaptative
morphological benefits,
and that excess Tip60
rescues an EE response in
AD flies.
oligomers
PP
31
Q
W
E4
31
Ti
p6
0
IS
O
Tip60 rescues EE induction of synaptic markers in
the AD neurodegenerative fly brain
Mushroom Body Structure
Assessment of changes in protein levels of pre- and postsynaptic marker components
EE response EE response
dampened in rescued in AD
flies with
2.5"
AD flies
excess Tip60
2"
1.5"
1"
**
Together, our studies demonstrate that the fly MB undergoes a beneficial
neuroadaptive response to EE and supports a critical role for Tip60 HAT action in
this process.
Reference
Q
;A
PP
W
E4
;A
W
T
Ti
p6
0
EE
IS
O
EE
W
T
;A
Ti
PP
p6
0
IS
O
A
Ti
PP
p6
0
A
PP
W
T
EE
Ti
p6
0
W
T
Q
31
Ti
p6
0
IS
O
EE
IS
O
W1
EE
Co-Immunoprecipitation
shows that APP
interacts with Tip60
through its C-terminus.
E4
Nucleus
11
8
Tip60
Transcriptional regulation
EE
AICD
Q
FE65
31
γ-Secretase
AICD
Mushroom(Body(Quan/ta/on(
E4
γ-Secretase
AICD
P3
IS
O
Ti
p6
0
β-Secretase
sAPPα
W1
11
8
Ti
p6
0
aβ
Full length
APP
α-Secretase
Area of Measurement
sAPPβ
Environmental,Enrichment
Tip60WT;APP
APP
PP
Amyloidogenic processing
Model for EE impact on cognitive function
;A
Tip60 interacts with APP C-terminal to form
Tip60-AICD complex
Summary
**
0.5"
*
**
**
**
*
**
0"
nc82%
BRP
ISO$APP$
dlg%
csp%
syx%
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Tip60 HAT Activity Mediates APP Induced Lethality and Apoptotic Cell Death in the
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EE$APP$
ISO$APPdTip60WT$ EE$APPdTip60WT$
Acknowledgement
This work was supported by NIH grant R01HD057939 to F.E.