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Centre for Molecular Medicine Norway, P.O. Box 1137, N-0318 University of Oslo, Norway www.ncmm.uio.no
Characterization of the role of CTCF in Estrogen Receptor dependent gene regulation. Elisa Fiorito1,*, Yogita Sharma1,*, Siv Gilfillan1, Baoyan Bai1, Alfonso Urbanucci2, Ian Mills2, Antoni Hurtado1,3
1 Breast Cancer Research Group, Center for Molecular Medicine, University of Oslo 2 Prostate Cancer Research Group, Center for Molecular Medicine, University of Oslo 3Department of Genetics, Institute for Cancer Research, University of Oslo
* These authors contributed equally to this work.
5
2
1
-1
0
1
2
3
4
-100
00
-920
0 -8
400
-760
0 -6
800
-600
0 -5
200
-440
0 -3
600
-280
0 -2
000
-120
0 -4
00
600
1400
22
00
3000
38
00
4600
54
00
6200
70
00
7800
86
00
9400
Bin
ding
inte
nsity
(ave
rage
)
CTCF sites lost (0h Estrogen unique)
CTCF 0h
CTCF 3h
-1
0
1
2
3
4
5
-100
00
-920
0 -8
400
-760
0 -6
800
-600
0 -5
200
-440
0 -3
600
-280
0 -2
000
-120
0 -4
00
600
1400
22
00
3000
38
00
4600
54
00
6200
70
00
7800
86
00
9400
Bin
ding
inte
nsity
(ave
rage
)
CTCF sites shared
-1
0
1
2
3
4
5
6
-100
00
-920
0 -8
400
-760
0 -6
800
-600
0 -5
200
-440
0 -3
600
-280
0 -2
000
-120
0 -4
00
600
1400
22
00
3000
38
00
4600
54
00
6200
70
00
7800
86
00
9400
Bin
ding
inte
nsity
(ave
rage
)
CTCF sites gained (3h Estrogen unique)
Estrogen stimulation redistributes CTCF binding at genome wide level CTCF ChIP-seq in MCF7 cells (first replicate):
Estrogen 0h Estrogen 3h
CTCF sites lost (1356 peaks)
CTCF sites not affected
(1256 peaks)
CTCF sites gained (5575 peaks)
-10kb +10kb
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!! !!! !!!!!!!!
!
!! !!!
0 50 100 150 200 250
50
10
01
50
20
02
50
30
0
E2_reg genes (newList)
GROSeq RPKM (0min)
GR
OS
eq
RP
KM
(1
60
min
)
!
!
!
!
!
!!
!!
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!
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!
!
top100Uptop100Down
Scalechr2:
i.1516i.1671i.987i.740i.678i.594i.453
i.6863i.4737i.5088i.5079i.4619i.3951i.3833i.3641i.3397i.3195i.5610i.5408i.5393i.5314i.5276i.3582i.3330i.910i.752
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GREB1GREB1
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H3K4me1_E
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H3K4me2_U
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H3K4me2_E
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H3K4me3_U
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H3K4me3_E
60 _
1 _
H3K27me3_U
50 _
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H3K27me3_E
50 _
1 _
H3K9Ac_U
25 _
1 _
H3K9Ac_E
25 _
1 _
H3K14Ac_U
20 _
1 _
H3K14Ac_E
20 _
1 _
DNase1_U
300 _
1 _
DNase1_E
300 _
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H3K14Ac_U
H3K14Ac_E
DNase1_U
DNase1_E
FAIRE_U
FAIRE_E
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UCSC Genes Based on RefSeq, UniProt, GenBank, CCDS and Comparative GenomicsE2F6E2F6E2F6E2F6E2F6E2F6
GREB1GREB1
GREB1GREB1
GREB1
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100 _
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GROSEQ_0m-
0 _
-100 _
GROSEQ_10m+
100 _
0 _
GROSEQ_10m-
0 _
-100 _
GROSEQ_25m+
100 _
0 _
GROSEQ_25m-
0 _
-100 _
GROSEQ_40m+
100 _
0 _
GROSEQ_40m-
0 _
-100 _
POLII_U
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1 _
POLII_E
40 _
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ER_U
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500 _
1 _
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1 _
FOXA1_E
60 _
1 _
AP2GAMMA_U
70 _
1 _
AP2GAMMA_E
70 _
1 _
p300_U
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1 _
p300_E
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CBP_U
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1 _
CBP_E
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1 _
SRC1_U
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1 _
SRC1_E
50 _
1 _
SRC2_U
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1 _
SRC2_E
400 _
1 _
SRC3_U
400 _
1 _
SRC3_E
400 _
1 _
H3K4me1_U
25 _
1 _
H3K4me1_E
25 _
1 _
H3K4me2_U
50 _
1 _
H3K4me2_E
50 _
1 _
H3K4me3_U
60 _
1 _
H3K4me3_E
60 _
1 _
H3K27me3_U
50 _
1 _
H3K27me3_E
50 _
1 _
H3K9Ac_U
25 _
1 _
H3K9Ac_E
25 _
1 _
H3K14Ac_U
20 _
1 _
H3K14Ac_E
20 _
1 _
DNase1_U
300 _
1 _
DNase1_E
300 _
1 _
FAIRE_U
10 _
1 _
FAIRE_E
10 _
1 _
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GROseq'Reads'160'min'
Scalechr2:
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DNase1_U
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UCSC Genes Based on RefSeq, UniProt, GenBank, CCDS and Comparative GenomicsE2F6E2F6E2F6E2F6E2F6E2F6
GREB1GREB1
GREB1GREB1
GREB1
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100 _
0 _
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0 _
-100 _
GROSEQ_10m+
100 _
0 _
GROSEQ_10m-
0 _
-100 _
GROSEQ_25m+
100 _
0 _
GROSEQ_25m-
0 _
-100 _
GROSEQ_40m+
100 _
0 _
GROSEQ_40m-
0 _
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ER_E
500 _
1 _
FOXA1_U
60 _
1 _
FOXA1_E
60 _
1 _
AP2GAMMA_U
70 _
1 _
AP2GAMMA_E
70 _
1 _
p300_U
30 _
1 _
p300_E
30 _
1 _
CBP_U
600 _
1 _
CBP_E
600 _
1 _
SRC1_U
50 _
1 _
SRC1_E
50 _
1 _
SRC2_U
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1 _
SRC2_E
400 _
1 _
SRC3_U
400 _
1 _
SRC3_E
400 _
1 _
H3K4me1_U
25 _
1 _
H3K4me1_E
25 _
1 _
H3K4me2_U
50 _
1 _
H3K4me2_E
50 _
1 _
H3K4me3_U
60 _
1 _
H3K4me3_E
60 _
1 _
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50 _
1 _
H3K27me3_E
50 _
1 _
H3K9Ac_U
25 _
1 _
H3K9Ac_E
25 _
1 _
H3K14Ac_U
20 _
1 _
H3K14Ac_E
20 _
1 _
DNase1_U
300 _
1 _
DNase1_E
300 _
1 _
FAIRE_U
10 _
1 _
FAIRE_E
10 _
1 _
CAMTA1&
GROseq'Reads'0'min'
GROseq'Reads'160'min'
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i.3472i.4945i.5086i.5522i.6256i.5275
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ChIAPET
UCSC Genes Based on RefSeq, UniProt, GenBank, CCDS and Comparative GenomicsP2RY2P2RY2P2RY2
P2RY2
P2RY6P2RY6P2RY6P2RY6
P2RY6P2RY6P2RY6
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GROSEQ_10m+
100 _
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-100 _
GROSEQ_25m+
100 _
0 _
GROSEQ_25m-
0 _
-100 _
GROSEQ_40m+
100 _
0 _
GROSEQ_40m-
0 _
-100 _
POLII_U
30 _
1 _
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30 _
1 _
ER_U
50 _
1 _
ER_E
50 _
1 _
FOXA1_U
30 _
1 _
FOXA1_E
30 _
1 _
AP2GAMMA_U
70 _
1 _
AP2GAMMA_E
70 _
1 _
p300_U
15 _
1 _
p300_E
15 _
1 _
CBP_U
150 _
1 _
CBP_E
150 _
1 _
SRC1_U
25 _
1 _
SRC1_E
25 _
1 _
SRC2_U
150 _
1 _
SRC2_E
150 _
1 _
SRC3_U
120 _
1 _
SRC3_E
120 _
1 _
H3K4me1_U
25 _
1 _
H3K4me1_E
25 _
1 _
H3K4me2_U
25 _
1 _
H3K4me2_E
25 _
1 _
H3K4me3_U
60 _
1 _
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60 _
1 _
H3K27me3_U
30 _
1 _
H3K27me3_E
30 _
1 _
H3K9Ac_U
15 _
1 _
H3K9Ac_E
15 _
1 _
H3K14Ac_U
20 _
1 _
H3K14Ac_E
20 _
1 _
DNase1_U
150 _
1 _
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150 _
1 _
FAIRE_U
10 _
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10 _
1 _
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ChIAPET
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P2RY2
P2RY6P2RY6P2RY6P2RY6
P2RY6P2RY6P2RY6
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100 _
0 _
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-100 _
GROSEQ_10m+
100 _
0 _
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GROSEQ_25m+
100 _
0 _
GROSEQ_25m-
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GROSEQ_40m+
100 _
0 _
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0 _
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30 _
1 _
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50 _
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50 _
1 _
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1 _
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30 _
1 _
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70 _
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70 _
1 _
p300_U
15 _
1 _
p300_E
15 _
1 _
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1 _
CBP_E
150 _
1 _
SRC1_U
25 _
1 _
SRC1_E
25 _
1 _
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150 _
1 _
SRC2_E
150 _
1 _
SRC3_U
120 _
1 _
SRC3_E
120 _
1 _
H3K4me1_U
25 _
1 _
H3K4me1_E
25 _
1 _
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25 _
1 _
H3K4me2_E
25 _
1 _
H3K4me3_U
60 _
1 _
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60 _
1 _
H3K27me3_U
30 _
1 _
H3K27me3_E
30 _
1 _
H3K9Ac_U
15 _
1 _
H3K9Ac_E
15 _
1 _
H3K14Ac_U
20 _
1 _
H3K14Ac_E
20 _
1 _
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150 _
1 _
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150 _
1 _
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10 _
1 _
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1 _
Scalechr11:
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FAIRE_U
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ChIAPET
UCSC Genes Based on RefSeq, UniProt, GenBank, CCDS and Comparative GenomicsP2RY2P2RY2P2RY2
P2RY2
P2RY6P2RY6P2RY6P2RY6
P2RY6P2RY6P2RY6
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100 _
0 _
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0 _
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GROSEQ_10m+
100 _
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GROSEQ_10m-
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-100 _
GROSEQ_25m+
100 _
0 _
GROSEQ_25m-
0 _
-100 _
GROSEQ_40m+
100 _
0 _
GROSEQ_40m-
0 _
-100 _
POLII_U
30 _
1 _
POLII_E
30 _
1 _
ER_U
50 _
1 _
ER_E
50 _
1 _
FOXA1_U
30 _
1 _
FOXA1_E
30 _
1 _
AP2GAMMA_U
70 _
1 _
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70 _
1 _
p300_U
15 _
1 _
p300_E
15 _
1 _
CBP_U
150 _
1 _
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150 _
1 _
SRC1_U
25 _
1 _
SRC1_E
25 _
1 _
SRC2_U
150 _
1 _
SRC2_E
150 _
1 _
SRC3_U
120 _
1 _
SRC3_E
120 _
1 _
H3K4me1_U
25 _
1 _
H3K4me1_E
25 _
1 _
H3K4me2_U
25 _
1 _
H3K4me2_E
25 _
1 _
H3K4me3_U
60 _
1 _
H3K4me3_E
60 _
1 _
H3K27me3_U
30 _
1 _
H3K27me3_E
30 _
1 _
H3K9Ac_U
15 _
1 _
H3K9Ac_E
15 _
1 _
H3K14Ac_U
20 _
1 _
H3K14Ac_E
20 _
1 _
DNase1_U
150 _
1 _
DNase1_E
150 _
1 _
FAIRE_U
10 _
1 _
FAIRE_E
10 _
1 _
PANK4&
4
0.0 0.5 1.0 1.5 2.0
0.0
0.2
0.4
0.6
0.8
1.0
Human : Mouse
Conservation (100 bp window)
Frac
tion
●●
●
●
●
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
●●●●●●●●●●●●●●●●●●●●●●
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
●●●●●●●●●●●●●●●●●●●●●●●
●●
●
●●●●●●●●●
●
●
CTCF 0 HourRandom Set
0.0 0.5 1.0 1.5 2.0 2.5
0.0
0.2
0.4
0.6
0.8
1.0
Human : Chicken
Conservation (100 bp window)
Frac
tion
●●
●
●
●
●●
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● ●●●●●●●●
●●
●
●
●
●
●●●●●●●●●●
●
●
CTCF 0 HourRandom Set
0 1 2 3 4
0.0
0.2
0.4
0.6
0.8
1.0
Human : Mouse
Conservation (100 bp window)
Frac
tion
●●
●●
●●●
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
●●
●
●
●
●
●●
●
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
●
●
CTCF 3 HourRandom Set
0 1 2 3 4 5 6
0.0
0.2
0.4
0.6
0.8
1.0
Human : Chicken
Conservation (100 bp window)
Frac
tion
●●
●
●●●●
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
●●
●●●●●●●●●●●●●●●
●
●
CTCF 3 HourRandom Set
0.0 0.5 1.0 1.5 2.0
0.0
0.2
0.4
0.6
0.8
1.0
Human : Mouse
Conservation (100 bp window)
Frac
tion
●●
●
●
●
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
●●●●●●●●●●●●●●●●●●●●●●
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
●●●●●●●●●●●●●●●●●●●●●●●
●●
●
●●●●●●●●●
●
●
CTCF 0 HourRandom Set
0.0 0.5 1.0 1.5 2.0 2.5
0.0
0.2
0.4
0.6
0.8
1.0
Human : Chicken
Conservation (100 bp window)
Frac
tion
●●
●
●
●
●●
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● ●●●●●●●●
●●
●
●
●
●
●●●●●●●●●●
●
●
CTCF 0 HourRandom Set
0 1 2 3 4
0.0
0.2
0.4
0.6
0.8
1.0
Human : Mouse
Conservation (100 bp window)
Frac
tion
●●
●●
●●●
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
●●
●
●
●
●
●●
●
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
●
●
CTCF 3 HourRandom Set
0 1 2 3 4 5 6
0.0
0.2
0.4
0.6
0.8
1.0
Human : Chicken
Conservation (100 bp window)
Frac
tion
●●
●
●●●●
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
●●
●●●●●●●●●●●●●●●
●
●
CTCF 3 HourRandom Set
3
GENE 1 GENE 2
Promoter Intergenic Gene body
-0,5 0
0,5 1
1,5 2
2,5 3
-100
00
-880
0 -7
600
-640
0 -5
200
-400
0 -2
800
-160
0 -4
00
1000
22
00
3400
46
00
5800
70
00
8200
94
00
Promoter regions
CTCF distribution around CTCF sites 0h overlapping with GRO-seq regions at 0 min
-0,5 0
0,5 1
1,5 2
2,5 3
-100
00
-860
0 -7
200
-580
0 -4
400
-300
0 -1
600
-200
14
00
2800
42
00
5600
70
00
8400
98
00
Non-promoter regions
CTCF 0h
CTCF 3h
CTCF distribution around CTCF sites 3h overlapping with GRO-seq regions at 160 min
-0,5 0
0,5 1
1,5 2
2,5 3
3,5 4
4,5 -1
0000
-8
600
-720
0 -5
800
-440
0 -3
000
-160
0 -2
00
1400
28
00
4200
56
00
7000
84
00
9800
Non-promoter regions
-0,5 0
0,5 1
1,5 2
2,5 3
3,5 4
-100
00
-860
0 -7
200
-580
0 -4
400
-300
0 -1
600
-200
14
00
2800
42
00
5600
70
00
8400
98
00
Promoter regions
●
●●
●
●
●
Prom
oter
prom
oter
Gen
eBod
y
Gen
ebod
y
Inte
rGen
ic
Inte
rgen
ic
0
5
10
15
20
25
CTC
F Bi
ndin
g Si
tes
●
●
CTCF 0 HourCTCF 3 Hour
Heatmap CTCF ChIP-seq
-0,5
0
0,5
1
1,5
2
2,5
-100
00
-880
0 -7
600
-640
0 -5
200
-400
0 -2
800
-160
0 -4
00
1000
22
00
3400
46
00
5800
70
00
8200
94
00
Non-promoter regions
Lamin B 0h
Lamin B 3h
-0,5 0
0,5 1
1,5 2
2,5
-100
00
-880
0 -7
600
-640
0 -5
200
-400
0 -2
800
-160
0 -4
00
1000
22
00
3400
46
00
5800
70
00
8200
94
00
Promoter regions
-0,5 0
0,5 1
1,5 2
2,5 3
3,5 4
-100
00
-880
0 -7
600
-640
0 -5
200
-400
0 -2
800
-160
0 -4
00
1000
22
00
3400
46
00
5800
70
00
8200
94
00
Non-promoter regions
-0,5 0
0,5 1
1,5 2
2,5 3
3,5 4
-100
00
-880
0 -7
600
-640
0 -5
200
-400
0 -2
800
-160
0 -4
00
1000
22
00
3400
46
00
5800
70
00
8200
94
00
Promoter regions
Lamin B distribution at CTCF sites 0h overlapping with GRO-seq regions at 0 min
Lamin B distribution at CTCF sites 3h overlapping with GRO-seq regions at 160 min
GRO-seq expression analysis
GRO-seq UP-regulated and down-regulated
genes containing CTCF binding sites (at 0h and
3h of estrogen treatment)
GRO-seq enrichment along gene body in UP and DOWN regulated gene
• GRO-seq expression validates the differences in enrichment of CTCF binding upon estrogen treatment
Genomic distribution of CTCF binding sites
9% CTCF sites 0h 8.5% CTCF sites 3h
41% CTCF sites 0h 38% CTCF sites 3h
50% CTCF sites 0h 53.5% CTCF sites 3h
Box-plots of GRO-seq overlapping CTCF binding sites in different genomic
locations
• More than 50% of CTCF binding sites are overlapping in intergenic regions, suggesting a possible role for CTCF as repressor or enhancer
• CTCF binding sites in intergenic regions correlate with GRO-seq expression
Conservation analysis of CTCF binding sites in intergenic regions
• CTCF binding sites are 90% conserved between human, mouse and chicken in 17% of cases at 0 hours and 26.5% of cases at 3 hours
Estrogen stimulation affects Lamin B distribution around CTCF sites overlapping with GRO-seq regions
• After estrogen treatment, lamin B binding intensity is reduced at promoter and non promoter regions overlapping with CTCF sites. • These data suggest an inverse correlation between CTCF and Lamin B binding.
CONCLUSIONS AND FUTURE PERSPECTIVES
• We observed a redistribution of CTCF chromatin interactions upon estrogen stimulation, suggesting a role for CTCF in estrogen dependent gene regulation.
• The combination of GRO-seq and CTCF binding analysis suggested that CTCF is regulating estrogen dependent transcription, possibly via the formation of different chromatin loops.
• The conservation and GRO-seq analysis detect the possibility of presence of active enhancers and repressors in CTCF mediated transcription regulation.
• Further, Lamin B and CTCF distribution suggest a role for nuclear remodeling in estrogen dependent gene regulation.
• Future analysis will prove the role of CTCF in chromatin loops involving enhancers and repressors. Further experiments (e.g. 3C) will validate our findings and shed light on the function of CTCF in the whole scenario.
![Study of Estrogen Receptor, Progesterone Receptor, …...[CANCER RESEARCH 49,4298-4304, August 1. 1989] Study of Estrogen Receptor, Progesterone Receptor, and the Estrogen-regulated](https://img.pdfslide.us/doc/110x75/5f95792bbdbd5e0915333803/study-of-estrogen-receptor-progesterone-receptor-cancer-research-494298-4304.jpg)
![Receptor aComplex · [CANCER RESEARCH 61, 3632–3639, May 1, 2001] Silencing and Reactivation of the Selective Estrogen Receptor Modulator-Estrogen Receptor aComplex1 Hong Liu, Eun-Sook](https://img.pdfslide.us/doc/110x75/60bc48b8ba9a3113a5631a2e/receptor-acomplex-cancer-research-61-3632a3639-may-1-2001-silencing-and-reactivation.jpg)
