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Cell cycle gene network in parental islets
B6
4wk
lean
B6 mice
4 wk
lean
ob
Btbr mice
10 wk
lean
ob
4 wk
lean
ob
10 wk
lean
ob
217 transcripts
Cell Cycle
Module
ob
10wk
lean
4wk
ob
lean
Btbr
ob
10wk
lean
ob
Cell cycle gene network in F2 islets
Cell Cycle
Module
overall islet network
Transcripts
131 transcripts
cell cycle module
500 F2-ob/ob mice
F2-ob #3372
F2-ob #3553
Ins = 77 ng/ml
Glu = 181 mg/dl
Ins = 1.7 ng/ml
Glu = 720 mg/dl
Cell cycle islet network stratifies F2 mice
Cell Cycle
Module
overall islet network
Transcripts
131 transcripts
cell cycle module
high
500 F2-ob/ob mice
21.4
275
428
54
169
5.2
low
insulin (ng/ml)
# islets/pancreas
glucose (mg/dl)
weight (gm)
TG (mg/dl)
C-peptide (pM)
5.6
175
517
46
290
2.9
The expression of Foxm1 and its target genes can predict metabolic phenotypes in F2
Leptinob/ob mice.
Davis D B et al. Molecular Endocrinology 2010;24:1822-1834
Cell cycle phases promoted by FoxM1 overexpression
Note lack of an effect of FoxM1 on G0G1 molecules.
Cell cycle phases promoted by FoxM1 overexpression
Mouse
Human
Obesity  FoxM1  proliferation
Cell cycle hot spot on Chr17 in F2 islets
Time course mice
F2 mice
B6
males
BTBR
females
Lean and obese
4 and 10 wks
B6 and BTBR
All obese
All 10 wks
F2s:
B6 vs BTBR alleles
All genes located at 25 – 45Mb on Chr17
Correlation between expression and proliferation vs insulin
Top negative and positive correlates…
Gene symbol
Tcf19
Pigq
Kifc1
Chtf18
Dpcr1
Nrm
Pxt1
Cchcr1
Tdrd6
Bat2
Trim40
Tbc1d22b
Zfp57
Gng13
Zfp811
Abcg1
Mcpt6
Apom
Angptl4
Cacna1h
Slc44a4
Hmga1
Runx2
Flot1
Zbtb12
Rhbdl1
Snf1lk
Rab40c
Rsph1
Rgl2
Psmb8
Itpr3
C2
Bat4
Enpp4
Daxx
Gene name
transcription factor 19
phosphatidylinositol glycan, class Q
kinesin family member C1
CTF18, chromosome transmission fidelity factor 18 homolog (S. cerevisiae)
diffuse panbronchiolitis critical region 1 (human)
nurim (nuclear envelope membrane protein)
peroxisomal, testis specific 1
coiled-coil alpha-helical rod protein 1
tudor domain containing 6
HLA-B associated transcript 2
tripartite motif-containing 40
TBC1 domain family, member 22B
zinc finger protein 57
guanine nucleotide binding protein 13, gamma
cDNA sequence BC052046
ATP-binding cassette, sub-family G (WHITE), member 1
mast cell protease 6
apolipoprotein M
angiopoietin-like 4
calcium channel, voltage-dependent, T type, alpha 1H subunit
solute carrier family 44, member 4
high mobility group AT-hook 1
runt related transcription factor 2
flotillin 1
zinc finger and BTB domain containing 12
rhomboid, veinlet-like 1 (Drosophila)
SNF1-like kinase
Rab40c, member RAS oncogene family
testis specific gene A2
ral guanine nucleotide dissociation stimulator-like 2
proteosome (prosome, macropain) subunit, beta type 8 (large multifunctional peptidase 7)
inositol 1,4,5-triphosphate receptor 3
complement component 2 (within H-2S)
HLA-B associated transcript 4
ectonucleotide pyrophosphatase/phosphodiesterase 4
Fas death domain-associated protein
Correlation
islet proliferation plasma insulin
0.528
0.497
0.476
0.466
0.461
0.458
0.456
0.451
0.436
0.432
0.431
0.43
0.423
0.422
0.42
0.42
0.408
0.389
-0.448
-0.402
-0.39
-0.373
-0.369
-0.367
-0.355
-0.346
-0.343
-0.342
-0.332
-0.331
-0.327
-0.32
-0.306
-0.304
-0.298
-0.29
0.41
0.679
0.371
0.657
0.657
0.368
0.569
0.644
0.625
0.623
0.594
0.619
0.629
0.617
0.616
0.457
0.625
0.561
-0.636
-0.6
-0.44
-0.442
-0.54
-0.532
-0.407
-0.39
-0.475
-0.402
-0.357
-0.385
-0.534
-0.468
-0.469
-0.332
-0.39
-0.333
http://msub.csbio.unc.edu/
BTBR and LP
B6
http://www.sanger.ac.uk/cgi-bin/modelorgs/mousegenomes/snps.pl
Coding SNPs, at Chr 17 locus, and correlated to D2O
Gene symbol
Kifc1
Ptk7
Tbc1d24
Chtf18
H2-M10.1
Olfr91
Dpcr1
Tdrd6
Abca17
Fpr-rs3
BC048355
Cbs
C230078M08Rik
Igfals
Unkl
2300002M23Rik
H2-M10.5
Pkmyt1
Ptcra
Cacna1h
Runx2
C330008L01Rik
Itpr3
Hcfc1r1
BC049807
Cd2ap
2310061I04Rik
Lrfn2
Supt3h
Cramp1l
2810417J12Rik
H2-Q2
H2-K1
Cul7
Trerf1
Mrps10
Gene name
kinesin family member C1
PTK7 protein tyrosine kinase 7
RIKEN cDNA C530046L02 gene
CTF18, chromosome transmission fidelity factor 18 homolog (S. cerevisiae)
histocompatibility 2, M region locus 10.1
olfactory receptor 91
diffuse panbronchiolitis critical region 1 (human)
tudor domain containing 6
ATP-binding cassette, sub-family A (ABC1), member 17
formyl peptide receptor, related sequence 3
cDNA sequence BC048355
cystathionine beta-synthase
RIKEN cDNA C230078M08 gene
insulin-like growth factor binding protein, acid labile subunit
unkempt-like (Drosophila)
RIKEN cDNA 2300002M23 gene
histocompatibility 2, M region locus 10.5
protein kinase, membrane associated tyrosine/threonine 1
pre T-cell antigen receptor alpha
calcium channel, voltage-dependent, T type, alpha 1H subunit
runt related transcription factor 2
RIKEN cDNA C330008L01 gene
inositol 1,4,5-triphosphate receptor 3
host cell factor C1 regulator 1 (XPO1-dependent)
cDNA sequence BC049807
CD2-associated protein
RIKEN cDNA 2310061I04 gene
leucine rich repeat and fibronectin type III domain containing 2
suppressor of Ty 3 homolog (S. cerevisiae)
Crm, cramped-like (Drosophila)
RIKEN cDNA 2810417J12 gene
histocompatibility 2, Q region locus 2
cullin 7
transcriptional regulating factor 1
mitochondrial ribosomal protein S10
Correlation
islet proliferation plasma insulin
0.476
0.469
0.467
0.466
0.466
0.464
0.461
0.436
0.43
0.429
0.407
0.373
0.338
0.334
0.317
0.315
0.306
0.299
-0.426
-0.402
-0.369
-0.321
-0.32
-0.294
-0.288
-0.271
-0.27
-0.257
-0.247
-0.245
-0.244
-0.243
-0.233
-0.231
-0.225
-0.219
0.433
0.768
0.691
0.643
0.572
0.639
0.652
0.63
0.681
0.64
0.491
0.555
0.198
0.384
0.508
0.535
0.423
0.273
-0.57
-0.571
-0.553
-0.493
-0.476
-0.22
-0.326
-0.285
-0.289
-0.312
-0.173
-0.288
-0.344
-0.386
-0.384
-0.283
-0.238
-0.225
JDRF gene selection
Effect of gene candidates on islet cell proliferation
incorporation
incorporation
3H-Thy
Rat islets
3H-Thy
Human islets
red, p<0.05 relative to Ad-GFP
title
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