Potential%20of%20Small%20Molecule%20Inducers%20in%20Cell-Based%20Therapeutics

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Potential of Small Molecule Inducers in
Cell-Based Therapeutics
Qiao Li, MD, PhD Department of Cellular and
Molecular Medicine Faculty of Medicine University
of Ottawa Ottawa, Ontario, Canada Qiao.Li_at_uOttawa
.ca
2014/10/28
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Muscle Wasting Disorder
Aging Cancer AIDS Congestive Heart Failure
Chronic Obstructive Pulmonary Diseases
Degenerating Cachexia inducing Mobility /
Neurogenic
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Myogenic Differentiation
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Transcriptional Coactivator p300
Bridge
FAT
Scaffold
HAT
Chen and Li. Epigenetics 2011
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Histone Acetylation Gene Activation
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Small molecule inducers
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Bex _at_ myogenic differentiation
Le May et al. JBC 2011
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ES cell differentiation
Le May et al. JBC 2011
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RA signaling _at_ a Pax3 DR5 locus
Le May et al. JBC 2011
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Cardiac and skeletal conversion
Li et al. Sci Rep 2013
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Pax3 in lineage specification
Li et al. Sci Rep 2013
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Cur _at_ myogenic differentiation
Day 4
Myf5 (fold)
MyoD (fold)
DMSO - RA -
-
Francetic et al. Mol Biol 2012
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The Myf5 Early Enhancer
Francetic et al. Mol Biol 2012
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Mechanisms of Specification
Chen and Li, Cell Bioscience 2013
Francetic and Li ,Transcription 2011
Le May et al. JBC 2011
Francetic et al. Mol Biol 2012
Li et al. Sci Rep 2013
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Cur _at_ MyoD gene expression
MyoD
MyHC
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Myoblast differentiation
-d0- -d1--d2--d3-
Myf5
MyoD mRNA (fold)
Myog
tubulin
1 2 3 4
Day 3
-D0- -D1- -D2-
Hamed et al. Sci Rep 2013
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Stepwise p300 association
Hamed et al. Sci Rep 2013
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Association of other HATs
Hamed et al. Sci Rep 2013
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Putative p300 recruiters
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HAT activity in myogenesis
Hamed et al. Sci Rep 2013
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H3K27 H3K18 acetylation
Hamed et al. Sci Rep 2013
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RNA-seq ChIP-seq
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Average phastCons
Distance from the center (bp)
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Correlation of the ChIP signals
R2 0.92
R2 0.89
R2 0.53
R2 0.46
H3K27ac (D)
H3K27ac (P)
H3K27ac (D)
H3K18ac (D)
H3K18ac (P)
H3K18ac (D)
H3K18ac (P)
H3K27ac (P)
R2 0.85
H3K27ac (D - P)
H3K18ac (D - P)
H3K27ac
H3K18ac
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ChIP signals around TSSs
H3K18ac
H3K27ac
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Motif analysis
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Conclusions
Chen and Li, Cell Bioscience 2013
Francetic and Li ,Transcription 2011
Le May et al. JBC 2011
Francetic et al. Mol Biol 2012
Hamed et al. Sci Rep 2013
Li et al. Sci Rep 2013
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Acknowledgments
Collaborators Dr. Alexandre Blais Dr. Nadine
Wiper-Bergeron Dr. Darryl Davis
The Li Lab Dr. Jihong Chen Ms. Munerah Hamed Mr.
Hamood AlSudais Ms. Katherine Dixon Ms. YuKa
Sai Ms. Ayse Ylibas Mr. William Nicola Dr.
Kawther Abed Dr. Yingjian Wang Ms. Melanie Le
May Ms. Tanja Francetic Ms. Natascha Lacroix Ms.
Saadia Khilji Mr. Hymn Mach Ms. Chenechen Hou
Cells Reagents Dr. Ilona Skerjanc Dr. Bernard
Jasmin