potential of small molecule inducers in cell-based therapeutics qiao li, md, phd department of...
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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
Muscle Wasting DisorderMuscle Wasting Disorder
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AgingCancer
AIDSCongestive Heart Failure
Chronic Obstructive Pulmonary Diseases
DegeneratingDegeneratingCachexia inducingCachexia inducingMobility / Mobility / Neurogenic Neurogenic
Myogenic Differentiation
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Chen and Li. Epigenetics 2011
Transcriptional Coactivator p300Transcriptional Coactivator p300
BridgeFAT ScaffoldHAT
Histone Acetylation & Gene ActivationHistone Acetylation & Gene Activation
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Small molecule inducers
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Bex @ myogenic differentiation
Le May et al. JBC 2011
ES cell differentiation
Le May et al. JBC 2011
RA signaling @ a Pax3 DR5 locus
Le May et al. JBC 2011
Cardiac and skeletal conversion
Li et al. Sci Rep 2013
Pax3 in lineage specification
Li et al. Sci Rep 2013
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
The Myf5 Early Enhancer
Francetic et al. Mol Biol 2012
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
Cur @ MyoD gene expression
MyHCMyoD
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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
Stepwise p300 association
Hamed et al. Sci Rep 2013
Association of other HATs
d0 d1 d2
tubulin
PCAF
1 2 3
CBP
Hamed et al. Sci Rep 2013
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
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HAT activity in myogenesis
Hamed et al. Sci Rep 2013
H3K27 & H3K18 acetylation
Hamed et al. Sci Rep 2013
RNA-seq & ChIP-seq
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Average phastCons
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Distance from the center (bp)
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)
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H3K27acH3K18ac
ChIP signals around TSSs
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H3K18ac
H3K27ac
Motif analysis
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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
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
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