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Anchel De Jaime-Soguero, Francesco Aulicino, Gokhan Ertaylan, Anna Griego, Aniello Cerrato, Aravind Tallam, Antonio del Sol, Maria Pia Cosma, Frederic Lluis
Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus
www.plosgenetics.org
www.plosgenetics.org
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(and)Tj
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(Tcf3)Tj
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(10)Tj
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(11)Tj
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(network)Tj
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(12)Tj
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4.405 0 Td
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6.1398 0 Td
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(the)Tj
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(pluripotency)Tj
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3.7077 0 Td
(Tcf1)Tj
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([)Tj
0.83 0.64 0.02 0 k
(14)Tj
0 g
(])Tj
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(and)Tj
1.7291 0 Td
(its)Tj
1.1452 0 Td
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(mESCs)Tj
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(determining)Tj
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(context-specific)Tj
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(signaling.)Tj
-23.2666 -1.3039 Td
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(somatic)Tj
3.3279 0 Td
(stem)Tj
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4.1556 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
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(canonical)Tj
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(Wnt)Tj
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(pathway)Tj
3.5717 0 Td
(stimulates)Tj
4.2576 0 Td
(cell)Tj
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(proliferation)Tj
-32.0142 -1.2983 Td
([)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(15)Tj
0 g
(])Tj
2.5511 0 Td
(mainly)Tj
2.9877 0 Td
(by)Tj
1.1849 0 Td
(inducing)Tj
3.7927 0 Td
(expression)Tj
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(of)Tj
/F15 1 Tf
1.0148 0 Td
[( )47(!)3()]TJ
/F9 1 Tf
2.5965 0 Td
(and)Tj
/F15 1 Tf
1.7348 0 Td
[()35(!)3()13()12()12()]TJ
2.6759 0 Td
[()]TJ
/F9 1 Tf
1.3776 0 Td
(genes)Tj
2.4435 0 Td
([)Tj
0.83 0.64 0.02 0 k
(16)Tj
0 g
(].)Tj
2.0749 0 Td
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4.0762 0 Td
(even)Tj
2.075 0 Td
(if)Tj
0.771 0 Td
(the)Tj
-35.824 -1.2983 Td
(mitogenic)Tj
4.2406 0 Td
(effects)Tj
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(of)Tj
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(the)Tj
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(pathway)Tj
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(somatic)Tj
3.3279 0 Td
(cells)Tj
1.9218 0 Td
(are)Tj
1.4514 0 Td
(well)Tj
1.8198 0 Td
(known,)Tj
3.2258 0 Td
(whether)Tj
3.4809 0 Td
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(signalling)Tj
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(the)Tj
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(cell)Tj
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(cycle)Tj
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(of)Tj
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(pluripotent)Tj
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(cells)Tj
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(remained)Tj
4.0365 0 Td
(unknown.)Tj
-19.5079 -1.2983 Td
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4.7848 0 Td
(mESCs,)Tj
3.3392 0 Td
(differently)Tj
4.354 0 Td
(to)Tj
1.0261 0 Td
(their)Tj
2.109 0 Td
(somatic)Tj
3.3278 0 Td
(stem)Tj
2.126 0 Td
(cell)Tj
1.5591 0 Td
(counterparts,)Tj
5.5275 0 Td
(display)Tj
3.0274 0 Td
(a)Tj
0.6519 0 Td
(unique)Tj
3.0217 0 Td
(and)Tj
-0.02 Tc
-36.0507 -1.2982 Td
(singular)Tj
3.3108 0 Td
(cell)Tj
1.4967 0 Td
(cycle)Tj
2.1089 0 Td
(defined)Tj
3.1181 0 Td
(by)Tj
1.1509 0 Td
(a)Tj
0.6349 0 Td
(fast)Tj
1.5364 0 Td
(proliferation)Tj
5.0627 0 Td
(rate,)Tj
1.8878 0 Td
(characterized)Tj
5.3518 0 Td
(by)Tj
1.1509 0 Td
(a)Tj
0.6349 0 Td
(long)Tj
1.9276 0 Td
(S)Tj
0.6803 0 Td
(phase)Tj
2.4037 0 Td
(and)Tj
1.6781 0 Td
(very)Tj
-34.1345 -1.3039 Td
(short)Tj
2.2053 0 Td
(G1)Tj
1.3776 0 Td
(and)Tj
1.6838 0 Td
(G2)Tj
1.3776 0 Td
(phases)Tj
2.7496 0 Td
([)Tj
0.83 0.64 0.02 0 k
(17)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(20)Tj
0 g
(].)Tj
3.4186 0 Td
(The)Tj
1.7348 0 Td
(high)Tj
1.9388 0 Td
(proliferative)Tj
4.8813 0 Td
(rate)Tj
1.6837 0 Td
(of)Tj
0.9865 0 Td
(mESCs)Tj
3.0274 0 Td
(is)Tj
0.8163 0 Td
(due)Tj
1.6498 0 Td
(to)Tj
0.9921 0 Td
(the)Tj
1.423 0 Td
(absence)Tj
3.2315 0 Td
(or)Tj
-35.1777 -1.2983 Td
(low)Tj
1.61 0 Td
(expression)Tj
4.303 0 Td
(of)Tj
0.9808 0 Td
(Cyclin-Dependent)Tj
7.37 0 Td
(Kinase)Tj
2.829 0 Td
(Inhibitors)Tj
4.0535 0 Td
(\(CDKIs\))Tj
3.5659 0 Td
(such)Tj
1.9956 0 Td
(as)Tj
0.9808 0 Td
(the)Tj
1.423 0 Td
(Ink4)Tj
2.0182 0 Td
(family)Tj
2.6306 0 Td
(members)Tj
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-33.7604 -1.2983 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 213.5622 165.4299 cm
BT
/F15 1 Tf
1 TL
-0.0266 Tc
0 0 Td
[()39()10()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 229.7196 161.0078 cm
BT
/F9 1 Tf
1 TL
-0.02 Tc
0 0 Td
(,)Tj
/F15 1 Tf
0.4308 0 Td
[( )]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 247.5779 165.4299 cm
BT
/F15 1 Tf
1 TL
-0.0266 Tc
0 0 Td
[()39()10(\n)]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 263.7921 161.0078 cm
BT
/F9 1 Tf
1 TL
-0.02 Tc
0 0 Td
(,)Tj
/F15 1 Tf
0.4308 0 Td
[(")]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 281.6503 165.4299 cm
BT
/F15 1 Tf
1 TL
-0.0266 Tc
0 0 Td
[()39()10()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 299.2251 161.0078 cm
BT
/F9 1 Tf
1 TL
-0.02 Tc
0 0 Td
(and)Tj
/F15 1 Tf
1.678 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 329.6125 165.4299 cm
BT
/F15 1 Tf
1 TL
-0.0266 Tc
0 0 Td
[()39()10()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 345.8834 161.0078 cm
BT
/F9 1 Tf
1 TL
-0.02 Tc
0 0 Td
(,)Tj
0.4308 0 Td
(the)Tj
1.423 0 Td
(CIP1/KIP)Tj
4.0308 0 Td
(family)Tj
2.6306 0 Td
(members)Tj
/F15 1 Tf
3.8381 0 Td
[(#)]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 482.9669 165.4299 cm
BT
/F15 1 Tf
1 TL
-0.0266 Tc
0 0 Td
[()13()10()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 496.0062 161.0078 cm
BT
/F9 1 Tf
1 TL
-0.02 Tc
0 0 Td
(,)Tj
/F15 1 Tf
0.4308 0 Td
[(#$)]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 513.9212 165.4299 cm
BT
/F15 1 Tf
1 TL
-0.0266 Tc
0 0 Td
[(%)30()10()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 529.285 161.0078 cm
BT
/F9 1 Tf
1 TL
-0.02 Tc
0 0 Td
(and)Tj
/F15 1 Tf
1.6837 0 Td
[($)]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 559.6724 165.4299 cm
BT
/F15 1 Tf
1 TL
-0.0266 Tc
0 0 Td
[(%)30()10(#)]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 148.0251 cm
BT
/F9 1 Tf
1 TL
-0.02 Tc
0 0 Td
([)Tj
0.83 0.64 0.02 0 k
(19)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(21)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(24)Tj
0 g
(],)Tj
4.5467 0 Td
(and)Tj
/F15 1 Tf
1.6781 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 275.8677 152.4472 cm
BT
/F15 1 Tf
1 TL
-0.0266 Tc
0 0 Td
[()30(\r)-23()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 287.1496 148.0251 cm
BT
/F9 1 Tf
1 TL
-0.02 Tc
0 0 Td
([)Tj
0.83 0.64 0.02 0 k
(25)Tj
0 g
(].)Tj
1.9955 0 Td
(The)Tj
/F15 1 Tf
1.7348 0 Td
[()39()10(&)30(\r)-23()]TJ
/F9 1 Tf
3.4696 0 Td
(locus)Tj
2.2053 0 Td
(encodes)Tj
3.3222 0 Td
(for)Tj
/F15 1 Tf
1.3436 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 441.411 152.4472 cm
BT
/F15 1 Tf
1 TL
-0.0266 Tc
0 0 Td
[()39()10()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 457.5685 148.0251 cm
BT
/F9 1 Tf
1 TL
-0.02 Tc
0 0 Td
(,)Tj
/F15 1 Tf
0.4251 0 Td
[( )]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 475.4267 152.4472 cm
BT
/F15 1 Tf
1 TL
-0.0266 Tc
0 0 Td
[()39()10(\n)]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 493.7952 148.0251 cm
BT
/F9 1 Tf
1 TL
-0.02 Tc
0 0 Td
(and)Tj
/F15 1 Tf
1.6837 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 524.2393 152.4472 cm
BT
/F15 1 Tf
1 TL
-0.0266 Tc
0 0 Td
[()30(\r)-23()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 533.3102 148.0251 cm
BT
/F9 1 Tf
1 TL
-0.02 Tc
0 0 Td
(,)Tj
0.4308 0 Td
(which)Tj
2.5682 0 Td
(are)Tj
-36.3285 -1.3039 Td
(considered)Tj
4.439 0 Td
(strong)Tj
2.6759 0 Td
(tumor)Tj
2.6646 0 Td
(suppressors.)Tj
4.9322 0 Td
(p15)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 361.3606 139.4645 cm
BT
/F9 1 Tf
1 TL
-0.0266 Tc
0 0 Td
(Ink4b)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 380.4661 134.9858 cm
BT
/F9 1 Tf
1 TL
-0.02 Tc
0 0 Td
(and)Tj
1.678 0 Td
(p16)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 411.4771 139.4645 cm
BT
/F9 1 Tf
1 TL
-0.0266 Tc
0 0 Td
(Ink4a)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 427.8614 134.9858 cm
BT
/F9 1 Tf
1 TL
-0.02 Tc
0 0 Td
(,)Tj
0.4251 0 Td
(along)Tj
2.3414 0 Td
(with)Tj
1.9333 0 Td
(the)Tj
1.4229 0 Td
(other)Tj
2.2677 0 Td
(Ink4)Tj
2.0183 0 Td
(and)Tj
1.6838 0 Td
(Cip/)Tj
-34.8772 -1.2982 Td
(Kip)Tj
1.6271 0 Td
(family)Tj
2.6362 0 Td
(members)Tj
3.8324 0 Td
(can)Tj
1.5761 0 Td
(slow)Tj
1.9559 0 Td
(down)Tj
2.4264 0 Td
(cell)Tj
1.491 0 Td
(proliferation)Tj
5.0627 0 Td
(by)Tj
1.1508 0 Td
(binding)Tj
3.2371 0 Td
(to)Tj
0.9921 0 Td
(and)Tj
1.6837 0 Td
(inhibiting)Tj
4.0252 0 Td
(CDK-cyclin)Tj
-31.6967 -1.2983 Td
(complexes.)Tj
4.4731 0 Td
(On)Tj
1.4796 0 Td
(the)Tj
1.423 0 Td
(other)Tj
2.2677 0 Td
(hand,)Tj
2.4038 0 Td
(expression)Tj
4.3029 0 Td
(of)Tj
/F15 1 Tf
0.9865 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 386.9291 113.4425 cm
BT
/F9 1 Tf
1 TL
-0.0266 Tc
0 0 Td
(Arf)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 398.7212 109.0204 cm
BT
/F9 1 Tf
1 TL
-0.02 Tc
0 0 Td
(inhibits)Tj
3.135 0 Td
(the)Tj
1.423 0 Td
(Mdm2)Tj
2.8687 0 Td
(E3)Tj
1.2359 0 Td
(ubiquitin)Tj
3.7927 0 Td
(ligase)Tj
2.3187 0 Td
(to)Tj
0.9978 0 Td
(acti-)Tj
-35.6425 -1.3039 Td
(vate)Tj
1.7631 0 Td
(and)Tj
1.6838 0 Td
(stabilize)Tj
3.2939 0 Td
(p53,)Tj
1.8481 0 Td
(which)Tj
2.5739 0 Td
(induces)Tj
3.1861 0 Td
(expression)Tj
4.303 0 Td
(of)Tj
0.9864 0 Td
(the)Tj
1.4172 0 Td
(CDKI)Tj
/F15 1 Tf
2.5739 0 Td
[(#)]TJ
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 449.8582 100.4598 cm
BT
/F15 1 Tf
1 TL
-0.0266 Tc
0 0 Td
[()13()10()]TJ
ET
Q
q
1 j
1 J
0 w
10 0 0 10 459.6094 95.9811 cm
BT
/F9 1 Tf
1 TL
-0.02 Tc
0 0 Td
(.)Tj
0.4251 0 Td
(Therefore,)Tj
4.235 0 Td
(the)Tj
/F15 1 Tf
1.423 0 Td
[()39()10(&)30(\r)-23()]TJ
/F9 1 Tf
3.4695 0 Td
(locus)Tj
-35.5121 -1.2982 Td
(controls)Tj
3.3562 0 Td
(the)Tj
1.4173 0 Td
(two)Tj
1.6611 0 Td
(main)Tj
2.2281 0 Td
(cell)Tj
1.4966 0 Td
(cycle)Tj
2.109 0 Td
(inhibitors)Tj
3.9855 0 Td
(and)Tj
1.6781 0 Td
(tumor)Tj
2.6645 0 Td
(suppressor)Tj
4.3824 0 Td
(pathways)Tj
3.7983 0 Td
([)Tj
0.83 0.64 0.02 0 k
(26)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(27)Tj
0 g
(].)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 133.6819 23.6976 re
W* n
q
133.6252 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 376.611 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(Distinct)Tj
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4.8982 0 Td
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[( )]TJ
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q
1 j
1 J
0 w
7.4999 0 0 6.6659 331.9937 516.8692 cm
BT
/F15 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[()39()10(\n)]TJ
ET
Q
q
1 j
1 J
0 w
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/F9 1 Tf
1 TL
-0.004 Tc
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/F15 1 Tf
0.4478 0 Td
[()]TJ
ET
Q
q
1 j
1 J
0 w
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/F15 1 Tf
1 TL
-0.0053 Tc
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[()30(\r)-23()]TJ
ET
Q
q
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(and)Tj
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1 J
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(Tcf3)Tj
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(14)Tj
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1.1792 0 Td
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3.549 0 Td
(\(WRE:)Tj
2.9423 0 Td
(5)Tj
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Q
q
1 j
1 J
0 w
6.9998 0 0 6.9998 329.8393 359.6031 cm
BT
/F16 1 Tf
1 TL
0 0 Td
(0)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 332.2204 355.9748 cm
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/F9 1 Tf
1 TL
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6.7634 0 Td
(W)Tj
1.1905 0 Td
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0.7994 0 Td
(A)Tj
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(previously)Tj
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(reported)Tj
3.6567 0 Td
([)Tj
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(34)Tj
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(,)Tj
0.83 0.64 0.02 0 k
(35)Tj
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(])Tj
-34.3953 -1.2982 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8199 0 Td
(1A)Tj
0 g
(\).)Tj
1.9445 0 Td
(We)Tj
1.6101 0 Td
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(that)Tj
1.7745 0 Td
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1.0262 0 Td
[()]TJ
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(5)Tj
1.2642 0 Td
(kb)Tj
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(the)Tj
1.4683 0 Td
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(start)Tj
1.9786 0 Td
(site)Tj
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(\(TSS\))Tj
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4.2407 0 Td
(genes)Tj
2.4434 0 Td
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0.83 0.64 0.02 0 k
(S1)Tj
1.508 0 Td
(Table)Tj
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3.0103 0 Td
(Accordingly)Tj
5.1363 0 Td
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(previous)Tj
3.6453 0 Td
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([)Tj
0.83 0.64 0.02 0 k
(13)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
(34)Tj
0 g
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3.2541 0 Td
(we)Tj
1.3266 0 Td
(found)Tj
2.6192 0 Td
(that)Tj
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(the)Tj
1.4683 0 Td
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(regions)Tj
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(known)Tj
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(targets)Tj
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[()3(')12(#)]TJ
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(,)Tj
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3.1634 0 Td
[()-3()1()]TJ
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2.4378 0 Td
(pluripotency)Tj
-31.2999 -1.304 Td
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2.5455 0 Td
(genes)Tj
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[(\()-6()-4()]TJ
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(,)Tj
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2.6192 0 Td
[()19(')]TJ
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(,)Tj
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2.4376 0 Td
[(\))28(\n)16()6()2()]TJ
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(\))Tj
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0.83 0.64 0.02 0 k
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(network,)Tj
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(lineage)Tj
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0.83 0.64 0.02 0 k
(8)Tj
0 g
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(Interestingly,)Tj
5.4935 0 Td
(we)Tj
1.3266 0 Td
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(that)Tj
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(a)Tj
0.6577 0 Td
(palindromic)Tj
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(Fig)Tj
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(1A)Tj
0 g
(\))Tj
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2.143 0 Td
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(Fig)Tj
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(1B)Tj
0 g
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(Among)Tj
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3.1521 0 Td
[()]TJ
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(3.5kb)Tj
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2.3527 0 Td
(40%)Tj
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(to)Tj
1.0262 0 Td
(promoter)Tj
4.0308 0 Td
(regions)Tj
3.1635 0 Td
(and)Tj
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(27%)Tj
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(intronic)Tj
3.4469 0 Td
(regions)Tj
3.1635 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8198 0 Td
(1C)Tj
0 g
(\).)Tj
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1.61 0 Td
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(1800)Tj
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(a)Tj
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(at)Tj
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0.9524 0 Td
[()]TJ
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(3)Tj
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(the)Tj
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(The)Tj
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-34.8545 -1.2983 Td
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(genes)Tj
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(increased)Tj
3.9967 0 Td
(up)Tj
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1.0261 0 Td
(2100)Tj
2.126 0 Td
(when)Tj
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(the)Tj
1.4684 0 Td
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3.3222 0 Td
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(extended)Tj
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1.0261 0 Td
[()]TJ
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(5)Tj
-35.5575 -1.3039 Td
(kb)Tj
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2.2053 0 Td
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1.7801 0 Td
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0.83 0.64 0.02 0 k
(S2)Tj
1.5137 0 Td
(Table)Tj
0 g
(\).)Tj
3.0047 0 Td
(Importantly,)Tj
5.2837 0 Td
(known)Tj
3.0047 0 Td
(Wnt)Tj
2.0296 0 Td
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(genes)Tj
2.4434 0 Td
(in)Tj
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(mESCs)Tj
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(such)Tj
2.058 0 Td
(as)Tj
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1.0148 0 Td
[()3(')12(#)]TJ
/F9 1 Tf
(,)Tj
/F15 1 Tf
-33.6867 -1.2983 Td
[()-3()1()]TJ
/F9 1 Tf
1.8709 0 Td
(and)Tj
/F15 1 Tf
1.7291 0 Td
[()-2(')]TJ
/F9 1 Tf
2.2677 0 Td
(were)Tj
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(identified)Tj
4.0592 0 Td
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(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8198 0 Td
(1D)Tj
0 g
1.4343 0 Td
(and)Tj
0.83 0.64 0.02 0 k
1.7292 0 Td
(S1A)Tj
1.8538 0 Td
(Fig)Tj
0 g
(\))Tj
1.8198 0 Td
(and)Tj
1.7348 0 Td
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2.3301 0 Td
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(vali-)Tj
-35.6709 -1.2982 Td
(dated)Tj
2.4322 0 Td
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1.1792 0 Td
(independent)Tj
5.2724 0 Td
(ChIP-qRT-PCR)Tj
6.5989 0 Td
(\()Tj
0.83 0.64 0.02 0 k
(Fig)Tj
1.8198 0 Td
(1E)Tj
0 g
(\).)Tj
-16.1062 -1.2983 Td
(Next)Tj
2.1373 0 Td
(we)Tj
1.3152 0 Td
(followed)Tj
3.6454 0 Td
(a)Tj
0.6406 0 Td
(reverse)Tj
3.0444 0 Td
(strategy)Tj
3.3164 0 Td
(to)Tj
1.0148 0 Td
(link)Tj
1.7688 0 Td
(a)Tj
0.6463 0 Td
(list)Tj
1.3833 0 Td
(of)Tj
1.0035 0 Td
(genes)Tj
2.4321 0 Td
(with)Tj
1.9899 0 Td
(the)Tj
1.4626 0 Td
(transcriptional)Tj
6.1002 0 Td
(machinery.)Tj
-33.0971 -1.3039 Td
(We)Tj
1.6101 0 Td
(used)Tj
2.058 0 Td
(the)Tj
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