A Family GenBank Ref Pseudo repFamily repClass repName Ref

HERV_H AJ289711.1 Laska and al, 2012 ENV59 LTR ERV1 HERVH-int

AJ289710.2 ENV60 LTR ERV1 HERVH-int

AJ289709.1 ENV62 LTR ERV1 HERVH-int

Jern and al, 2005 Pol62 LTR ERV1 HERVH-int

HERV_K (HML-2) LTR AF333072.2 Tai and al, 2008 K18 ERV1 HERVK-int

AF164610.1 LTR HERVK-int Christensen, 2005 K102 ERV1

HERV_W AF072506.2 Mameli and al, 2007 ERVWE1 HERV17-int/LTR17 ERV1 HERVW-int

B Digital dropplet PCR

160 8

140 7 Jurkat cells (near diploid) 120 6 HAP1 cells (haploid)

100 5

80 4

60 3

40 2

20 1 DNA copy number per 0 0 env env env env env LTR pol LTR Sat2 fos IL8

59 60 102 62 62 62 18 - TNF c chr11 FOSB TGFb1 H K W H K RPLP0

HERV HERV Promoters

H7 K20

C BpV(pic) 8 Vehicle D 90 Vehicle ** 30' *** ** 30' 60' 6 60' 60 ** *** 4 *** * *** ** *** * 30 andRPLP0 andRPLP0 2 ***

***

0 0 TGFβ env59 env60 env62 pol62 LTR-K18 env-K102 env TNF IL8 Fold change in RNA levels relative vehicleto Foldchange in RNA Fold change in RNA levels relative vehicleto Foldchange in RNA Control HERV_H HERV_K HERV_W Cytokines

Figure S1 E Live cells/mL Dead cells %

DMSO 1h 87.104 0%

Dieldrin in DMSO 30 min. 85.104 0%

Dieldrin in DMSO 1h 92.104 2%

Vehicle F 8 Dieldrin * 30' C 7 60'

6

5

4

3 RPLP0

2

1

0 CYP1A1 CYP1B1 NQO1 GCLC GCLM SLC6A12 SLC5A3 AKR1B1 H2AFX CDKN1A BAX VEGF DNAJB9 MT1E MT2A HSP90B1 HSPA6 Fold change in RNA levels relative vehicleto and Foldchange in RNA Environmental Oxidative stress Osmotic stress DNA damage Hypoxia ER stress Metal Stress Heat Shock stress G 8 Vehicle PMA 30' 7 60'

6 ** 5

4

3 RPLP0

2

1

0 CYP1A1 CYP1B1 NQO1 GCLC GCLM SLC6A12 SLC5A3 AKR1B1 H2AFX CDKN1A MDM2 BAX VEGF DNAJB9 MT1E MT2A HSP90B1 HSPA6 Fold change in RNA levels relative vehicleto and Foldchange in RNA Environmental Oxidative stress Osmotic stress DNA damage Hypoxia ER stress Metal Stress Heat Shock stress

Figure S1 H DAPI TRIM28S584p HP1γ

DMSO

Dieldrin

Camptotecin

2μ

Figure S1 A

DMSO

Dieldrin

PMA

B

DMSO 30' 60000 Dieldrin 30'

PMA 30'

50000

40000

30000

20000

10000

0 T68 T60 S46 S15 S63 Y411 Y411 T183 T308 T172 T389 T246 T198 S392 S473 S133 Y419 Y397 Y394 Y689 Y694 Y397 Y751 S727 Y402 Y420 Y426 Y412 Y641 Y699 Y705 Y783 S1177 S1177 Y1086 S2448 S21/S9 S78/S82 T180/Y182 T421/S424 S376/S360 Y694/Y699 S380/S386/S377 T202/Y204, T185/Y187 T202/Y204, T221/Y223 T183/Y185, Ref Spot p38 ERK1/2 JNK1/2/3 GSK3 α/β p53 Ref Spot EGFR MSK1/2 AMPK α1 Akt 1/2/3 Akt 1/2/3 p53 TOR CREB AMPK α2 β Catenin p70 S6 p53 c-jun Src Lyn Lck STAT2 STAT5a p70 S6 RSK 1/2/3 eNos Hck ChK2 FAK PDGF Rβ STAT 5a/b STAT3 WNK1 PYK2 Ref Spot PRAS 40 HSP60 Fyn Yes Fgr STAT6 STAT5b STAT3 p27 PLC-γ1 kinase kinase

C HERV_H_env62 D TNF E C-jun F FosB G cFos *** 4 600 250 90 ** ** 3 40 200 400 60 150 2 20 100 200 1 30 50 vehicleand RPLP0 vehicleand RPLP0 vehicleand RPLP0 vehicleand RPLP0 vehicleand RPLP0

0 PD98059

0 PD98059 0 PD98059

0 PD98059

0 PD98059

Fold change in RNA levels relative to Foldchange in RNA Fold change in RNA levels relative to Foldchange in RNA levels relative to Foldchange in RNA Fold change in RNA levels relative to Foldchange in RNA Fold change in RNA levels relative to Foldchange in RNA

Vehicle Dieldrin Vehicle Dieldrin Vehicle Dieldrin Vehicle Dieldrin Vehicle Dieldrin

Figure S2 A Dimethylation of H3K9 B Vehicle 4,0 BIX treatment 16h Vehicle 3,0 0,1 µM 0,1 µM 1 µM 1 µM

3,0 10 µM 10 µM 2,0 ** ** 2,0 **

1,0 andRPLP0 andRPLP0 1,0

0,0 0,0 TGFβ env59 env60 env62 pol62 LTR-K18 env-K102 env Sat2 TNF IL8 Fold change in mRNA levels relatifvehicle to Foldchange in mRNA Fold change in mRNA levels relatifvehicle to Foldchange in mRNA Control HERV_H HERV_K HERV_W Satellite Cytokines

C DNA methylation D H19 locus Azadesoxycitidine treatment 16h 40" *** Vehicle 6,0 Vehicle 15,0 0,1 µM H19$$ 0,1 µM 1 µM 40" 1 µM 10 µM 30" 10 µM 4,0 10,0 * 30" 20" 20"

** C(t)" 2,0 5,0 C(t)" andRPLP0 andRPLP0 10" 10"

0,0 0" 0" 0,0 TGFβ env59 env60 env62 pol62 LTR-K18 env-K102 env Sat2 '" TNF IL8 Fold change in mRNA levels relatifvehicle to Foldchange in mRNA

Fold change in mRNA levels relatifvehicle to Foldchange in mRNA '" Control HERV_H HERV_K HERV_W Satellite Cytokines 1"μM" 0,1"μM" 10"μM" 1"μM" 0,1"μM" 10"μM"

E DNA methylation F Trimethylation of H3K9 Azadesoxycitidine treatment 16h Chaetocin treatment 0.1μM 15 Vehicle * 25 0,1 µM Vehicle * 30' 1 µM ** 60' 10 µM 20 240' 16h 10 15

* * * ** 10 5 RPLP0 andRPLP0 ** 5

0 0 TNF IL8 Fold change in RNA levels relative vehicleto and Foldchange in RNA

Fold change in RNA levels relative vehicleto Foldchange in RNA TGFß c-jun c-fos FosB Cytokines

Figure S3 A B TNFAIP6 12 CD83 12 B *** *** 9 9

*** 6 6 *** RPLP0 ** RPLP0 *** 3 *** 3 ***

0 0 - 30' 60' - 30' 60' - 30' 60' - 30' 60' Fold change in RNA levels relative vehicleto and Foldchange in RNA

Dieldrin PMA levels relative vehicleto and Foldchange in RNA Dieldrin PMA

C Table showing values for repressed mentioned in the text

D Panel showing that when reads with 20As overlap with HERVs, their A tract is mostly encoded by the geneome.

Figure S4 A HERVd annotation assembles HERVs fragmented in RepeatMasker : example

B

Divergent transcription Divergent transcription Dieldrin

DMSO

HERVd FOS

ENCODE TF

C D Dieldrin Divergent transcription activated by dieldrin DMSO Divergent transcription activated by dieldrin HERVd CLHC1 Dieldrin

ENCODE DMSO TF

HMGCR HERVd

E

GO Biol. Process. on genes in proximity of HERVs showing divergent transcription activated at least 2-fold by dieldrin

Figure S5 F Example of a transcription factor in HERV-free zone: MYC. Note the increased elongation in the presence of dieldrin.

DMSO End of promoter transcription End of transcription

Dieldrin Last HERV First HERV

RepMa MYC HERVd

G Distribution of HERV densities in transcription factor genes and other genes (in %)

Figure S5