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Potential of Small Molecule Inducers in Cell-Based
TherapeuticsQiao Li, MD, PhDQiao Li, MD, PhDDepartment of Cellular and Department of Cellular and Molecular MedicineMolecular MedicineFaculty of MedicineFaculty of MedicineUniversity of OttawaUniversity of OttawaOttawa, Ontario, CanadaOttawa, Ontario, Canada
[email protected]@uOttawa.ca
2014/10/28 QL
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Muscle Wasting DisorderMuscle Wasting Disorder
QL
AgingCancer
AIDSCongestive Heart Failure
Chronic Obstructive Pulmonary Diseases
DegeneratingDegeneratingCachexia inducingCachexia inducingMobility / Mobility / Neurogenic Neurogenic
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Myogenic Differentiation
QL
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Chen and Li. Epigenetics 2011
Transcriptional Coactivator p300Transcriptional Coactivator p300
BridgeFAT ScaffoldHAT
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Histone Acetylation & Gene ActivationHistone Acetylation & Gene Activation
QL
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Small molecule inducers
QL
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Bex @ 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 @ 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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0
6
12
18
Cur @ myogenic differentiation
Francetic et al. Mol Biol 2012
0
60
120
DMSO + + Curcum - +
HA
T a
ctiv
ity
*
DMSO - + + RA - - +
Day 4
Myf
5 (f
old
)M
yoD
(fo
ld)
0
6
12
18
1 2 3
tubulin
Myog
DMSO - + + RA - + + Cur - - +
MyHC
MyoD
MyHC
Myf5
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The Myf5 Early Enhancer
Francetic et al. Mol Biol 2012
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Mechanisms of Specification
Francetic et al. Mol Biol 2012
Le May et al. JBC 2011
Francetic and Li ,Transcription 2011
Chen and Li, Cell & Bioscience 2013
Li et al. Sci Rep 2013
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Cur @ MyoD gene expression
MyHCMyoD
QL
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Myoblast differentiation
Day 3
-d0- -d1--d2--d3-
tubulin
1 2 3 4
Myog
Myf5
My
oD
mR
NA
(fo
ld)
-D0- -D1- -D2-0
10
20
30
- 6 kb- 20 kb
CER PRRDRR
Myod1 locus
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
d0 d1 d2
tubulin
PCAF
1 2 3
CBP
Hamed et al. Sci Rep 2013
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Putative p300 recruiters
- CER - - DRR - - PRR -
Six
1
(Fo
ld)
0
2
4
6
d1
d0
d2
p300
Six1
p300 IP
Input IgG IP
Six1 IP
IgG IP
QL
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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
QL
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Average phastCons
QL
Distance from the center (bp)
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Correlation of the ChIP signalsH
3K27
ac (
P)
H3K
27ac
(D
)H3K18ac (P)
R2 = 0.92
H3K18ac (D)
H3K
27
ac (
D -
P)
R2 = 0.85
H3K
18ac
(D
)
H3K
27ac
(D
)
H3K18ac (P) H3K27ac (P)
R2 = 0.89 R2 = 0.53R2 = 0.46
H3K18ac (D - P)
QL
H3K27acH3K18ac
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ChIP signals around TSSs
QL
H3K18ac
H3K27ac
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Motif analysis
QL
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Conclusions
Francetic et al. Mol Biol 2012
Le May et al. JBC 2011
Francetic and Li ,Transcription 2011
Hamed et al. Sci Rep 2013
Chen and Li, Cell & Bioscience 2013
Li et al. Sci Rep 2013
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Cells & ReagentsCells & ReagentsDr. Ilona SkerjancDr. Ilona SkerjancDr. Bernard JasminDr. Bernard Jasmin
CollaboratorsCollaboratorsDr. Alexandre BlaisDr. Alexandre BlaisDr. Nadine Wiper-Dr. Nadine Wiper-BergeronBergeronDr. Darryl DavisDr. Darryl Davis
AcknowledgmentsAcknowledgments
The Li LabThe Li LabDr. Dr. Jihong ChenJihong Chen
Ms. Ms. Munerah HamedMunerah Hamed
Mr. Mr. Hamood AlSudaisHamood AlSudais
Ms. Ms. Katherine DixonKatherine Dixon
Ms. YuKa SaiMs. YuKa Sai
Ms. Ayse YlibasMs. Ayse Ylibas
Mr. William NicolaMr. William Nicola
Dr. Kawther AbedDr. Kawther Abed
Dr. Yingjian WangDr. Yingjian Wang
Ms. Ms. Melanie Le MayMelanie Le May
Ms. Ms. Tanja FranceticTanja Francetic
Ms. Ms. Natascha Lacroix Natascha Lacroix
Ms. Ms. Saadia KhiljiSaadia Khilji
Mr. Mr. Hymn MachHymn Mach
Ms. Ms. Chenechen HouChenechen Hou
QL