Repression of Tip60 cogni0on-­‐linked gene expression in APP induced neurodegenera0ve Drosophila brain is relieved by increased Tip60 HAT levels Priyalakshmi Panikker and Felice Elefant
Department of Biology, Drexel University, Philadelphia PA 19104
Repression of Tip60 cognition-linked gene relieved by excess Tip60 HAT
levels Background
Mechanism by which Tip60 regulates expression of neuroprotective
genes
Neurodegenerative diseases are often associated with defects in gene expression profiles
linked to learning and memory, resulting in cognitive impairment.
Epigenetic machinery is essential for proper cognitive
function. Histone acetylation is one such epigenetic
chromatin modification that promotes transcriptional
regulation in neurons that influences memory and
learning.
Tip60 can act as a co-activator
However, the select cognition linked histone
acetyltransferase (HAT) enzymes that generate these
epigenetic marks remain largely unknown. Tip60 is one
such HAT shown by our laboratory to play a critical role
in regulating neuronal genes linked to
cognition(Genetics, 2007; PLoS ONE, 2010; PLoS ONE,
2011, PloS ONE, 2012).
We have shown that Tip60 HAT activity restores function in a number of cognition associated
neuronal circuits negatively affected in an Alzheimer’s disease (AD) Drosophila model.
Tip60 can act as a co-repressor
qPCR performed on cDNA isolated from staged 3rd instar larval brain tissue from larvae
expressing APP or APP;Tip60WT under elavC155 pan-neuronal GAL4 driver.
Identification of transcription factors that recruit Tip60 to
neuroprotective genes
Clusters of cognition
linked genes have
enrichment for
common TFs linked to
neuronal function.
These pilot studies
support a model by
which Tip60 controls
neuroprotective gene
sets in concert via its
simultaneous
recruitment to these
loci by common neural
TFs.
Zhu et al., 2007
Here, we hypothesize that Tip60 functions in neuroprotection by beneficially epigenetically
reprogramming gene expression programs essential for maintaining neuronal health and
higher order brain function.
Our Findings should provide new insight into novel Tip60 HAT based neuroprotective
mechanisms in neurological disorders.
Tip60 and Alzheimer’s Disease
Tip60 has been implicated in the age-related neurodegenerative disorder Alzheimer’s
disease (AD) via its interaction with the AD linked amyloid precursor protein intracellular
domain (AICD).
Transcription factor (TF) motifs significantly enriched within promoters of Tip60 cognition linked gene
loci. TF motifs were identified using the MEME-Chip platform. Significance values for each discovered motif are
represented as p-value, and the matching TF motif is shown for each gene.
Non-amyloidogenic
processing
Amyloidogenic processing
oligomers
sAPPβ
aβ
sAPPα
Full length
APP
β-Secretase
α-Secretase
Tip60 and gene repression
P3
Future Directions
γ-Secretase
γ-Secretase
AICD
AICD
•  Dissect epigenetic based mechanisms underlying Tip60 HAT action in neuroprotective gene control.
FE65
AICD
Tip60
Nucleus
Transcriptional regulation
The APP-Tip60 complex is recruited to the promoters of certain target genes where it acts to
acetylate select histone proteins to epigenetically regulate gene transcription.
Studies have shown that Tip60 can serve as a co-repressor to silence specific-genes. Here we are
hypothesizing that excess Tip60 in our AD flies suppresses apoptosis in fly brain by repressing genes that are
responsible for inducing apoptosis.
Effect of excess Tip60 HAT levels on selected
apoptosis-related genes
Inappropriate complex formation and/or recruitment may contribute or lead to AD pathology
via misregulation of target genes required for neurogenesis. Previous research from our lab has
identified dysregulation of Tip60 HAT
activity as a contributing factor to
early neuronal dysfunction in our AD
fly models. Additionally, our lab has
also discovered that increasing Tip60
HAT levels in an AD
neurodegenerative fly model rescues
impaired cognition linked neural
circuits.
Pirooznia and Elefant, 2013
Pirooznia, 2012b
Confocal images of neuronal apoptosis visualized by
TUNEL staining of brains from staged third instar
larvae expressing indicated transgenes driven by
pan-neuronal driver 179-GAL4.
•  Identify Tip60 interacting factors required for regulating neuroprotective gene expression.
References
Lorbeck, M., et al, 2011. Microarray Analysis Uncovers a Role for Tip60 in Nervous System Function and General
Metabolism. PLoS One 6, 14.
Pirooznia, S., et al, 2012b. Tip60 HAT Activity Mediates APP Induced Lethality and Apoptotic Cell Death in the CNS of a
Drosophila Alzheimer’s Disease Model. Plos 7, e41776.
Pirooznia, S., Elefant, F., 2013. Targeting specific HATs for neurodegenerative disease treatment: Translating basic biology
to therapeutic possibilities. Front Cell Neurosci; 7: 30
Sarthi, J., Elefant, F., 2011. dTip60 HAT activity controls synaptic bouton expansion at the Drosophila neuromuscular
junction. PLoS One 6, e26202.
Zhu, X., et al., 2007. The cloning and characterization of the histone acetyltransferase human homolog Dmel\TIP60 in
Drosophila melanogaster: Dmel\TIP60 is essential for multicellular development. Genetics 175, 1229-1240.
Acknowledgement
This work was supported by NIH grant R01HD057939 to F.E.