Additional material Table S1. List of the

Additional material Table S1. List of the hypermethylated genes in placental tissue identified by MIRA based microarray

Gene

Total number of Probes

Number of upgraded probes

PITX2 PAX6 NR2F2 MNX1 TLX3 PAX9 SALL1 MAD1L1 TBX3 HLX PDX1

83 145 96 33 66 58 75 186 87 72 58

27 20 17 15 15 15 15 14 14 14 13

TFAP2C

77

13

70 59 46 100

12 12 12 10

98

10

OSR1 PTGER4 ONECUT2 ADRA1A HOXA6 POU4F2 TBX5 NKX2-2 TLX1 HAND1 MSX1 WT1

60 23 78 28 39 44 67 146 57 46 85 52

10 10 10 10 10 9 9 9 9 8 8 8

SLC12A7

93

8

FOXC1 NR5A2 PHOX2B CCND2

78 46 31 59

8 8 8 7

SIX1 SIM1 OTX2 CBX4 TFAP2A

Gene description

Paired-like homeodomain 2 Paired box 6 Nuclear receptor subfamily 2, group F, member 2 Motor neuron and pancreas homeobox 1 T-cell leukemia homeobox 3 Paired box 9 Sal-like 1 (Drosophila) MAD1 mitotic arrest deficient-like 1 (yeast) T-box 3 H2.0-like homeobox Pancreatic and duodenal homeobox 1 Transcription factor AP-2 gamma (activating enhancer binding protein 2 gamma) SIX homeobox 1 Single-minded homolog 1 (Drosophila) Orthodenticle homeobox 2 Chromobox homolog 4 (Pc class homolog, Drosophila) Transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha) Odd-skipped related 1 (Drosophila) Prostaglandin E receptor 4 (subtype EP4) One cut homeobox 2 Adrenergic, alpha-1A-, receptor Homeobox A6 POU class 4 homeobox 2 T-box 5 NK2 homeobox 2 T-cell leukemia homeobox 1 Heart and neural crest derivatives expressed 1 Msh homeobox 1 Wilms tumor 1 Solute carrier family 12 (potassium/chloride transporters), member 7 Forkhead box C1 Nuclear receptor subfamily 5, group A, member 2 Paired-like homeobox 2b Cyclin D2

OLIG2 DLX4 PKD1

82 61 130

7 7 7

TFAP2B

47

7

PITX1 MEIS1 LMX1A ROR2

52 79 56 51

7 7 7 7

PDGFRA

75

7

WIT1 EN2 SOX1 TSSC1 SOX9 NR4A3 BAI2 WNT5A HSF4

29 109 65 44 71 73 43 66 53

7 6 6 6 6 6 6 6 6

31

6

85 55 103 22 34 51 20 37 61 14 50 33 56 70 49 34 37 69 24 52 17 26

6 6 6 6 6 6 6 6 6 6 6 5 5 5 5 5 5 5 5 5 5 5

GAD2 GATA2 FOXF2 LHX2 HOXB13 CD8A DLEU2 GRID2 HOXA9 HOXD3 CUL4A TOLLIP GNG4 ADCYAP1 FOXA1 AXIN1 PTRF IRS1 FOXB1 EPHA7 BCL2L11 AVPR1A SLC30A3

Oligodendrocyte lineage transcription factor 2 Distal-less homeobox 4 Polycystic kidney disease 1 (autosomal dominant) Transcription factor AP-2 beta (activating enhancer binding protein 2 beta) Paired-like homeodomain 1 Meis homeobox 1 LIM homeobox transcription factor 1, alpha Receptor tyrosine kinase-like orphan receptor 2 Platelet-derived growth factor receptor, alpha polypeptide Wilms tumor upstream neighbor 1 Engrailed homeobox 2 SRY (sex determining region Y)-box 1 Tumor suppressing subtransferable candidate 1 SRY (sex determining region Y)-box 9 Nuclear receptor subfamily 4, group A, member 3 Brain-specific angiogenesis inhibitor 2 Wingless-type MMTV integration site family, member 5A Heat shock transcription factor 4 Glutamate decarboxylase 2 (pancreatic islets and brain, 65kda) GATA binding protein 2 Forkhead box F2 LIM homeobox 2 Homeobox B13 CD8a molecule Deleted in lymphocytic leukemia 2 (non-protein coding) Glutamate receptor, ionotropic, delta 2 Homeobox A9 Homeobox D3 Cullin 4A Toll interacting protein Guanine nucleotide binding protein (G protein), gamma 4 Adenylate cyclase activating polypeptide 1 (pituitary) Forkhead box A1 Axin 1 Polymerase I and transcript release factor Insulin receptor substrate 1 Forkhead box B1 EPH receptor A7 BCL2-like 11 (apoptosis facilitator) Arginine vasopressin receptor 1A Solute carrier family 30 (zinc transporter), member 3

CYP24A1 CYP1B1 HOXA1

17 35 28

5 5 5

KCNA1

28

5

TLX2 FGF12 NKX2-1 TAL1 GAD1 GRIA2 RORA FOXJ1 KLF9 SLIT2 ISL1 NKD1 FGF8 HOXC5 RPS6KA2 CCNA1 DLX2 SNTG1

36 34 25 34 64 17 46 29 45 37 44 19 18 26 48 12 74 12

5 5 5 5 5 5 4 4 4 4 4 4 4 4 4 4 4 4

GNA11

43

4

ZFP36L2 HOXB8 NPY GRIA3 DLL4 CGB7 A2BP1 HTR1B POU4F3 MYF6 TCF7 HOXB2 AVP FLI1 GFRA2

30 42 17 16 72 13 50 18 40 9 11 36 20 47 32

4 4 4 4 4 4 4 4 4 4 4 4 4 3 3

CTDP1

88

3

PTBP1 SKI

66 97

3 3

Cytochrome P450, family 24, subfamily A, polypeptide 1 Cytochrome P450, family 1, subfamily B, polypeptide 1 Homeobox A1 Potassium voltage-gated channel, shaker-related subfamily, member 1 (episodic ataxia with myokymia) T-cell leukemia homeobox 2 Fibroblast growth factor 12 NK2 homeobox 1 T-cell acute lymphocytic leukemia 1 Glutamate decarboxylase 1 (brain, 67kda) Glutamate receptor, ionotropic, AMPA 2 RAR-related orphan receptor A Forkhead box J1 Kruppel-like factor 9 Slit homolog 2 (Drosophila) ISL LIM homeobox 1 Naked cuticle homolog 1 (Drosophila) Fibroblast growth factor 8 (androgen-induced) Homeobox C5 Ribosomal protein S6 kinase, 90kda, polypeptide 2 Cyclin A1 Distal-less homeobox 2 Syntrophin, gamma 1 Guanine nucleotide binding protein (G protein), alpha 11 (Gq class) Zinc finger protein 36, C3H type-like 2 Homeobox B8 Neuropeptide Y Glutamate receptor, ionotrophic, AMPA 3 Delta-like 4 (Drosophila) Chorionic gonadotropin, beta polypeptide 7 Ataxin 2-binding protein 1 5-hydroxytryptamine (serotonin) receptor 1B POU class 4 homeobox 3 Myogenic factor 6 (herculin) Transcription factor 7 (T-cell specific, HMG-box) Homeobox B2 Arginine vasopressin Friend leukemia virus integration 1 GDNF family receptor alpha 2 CTD (carboxy-terminal domain, RNA polymerase II, polypeptide A) phosphatase, subunit 1 Polypyrimidine tract binding protein 1 V-ski sarcoma viral oncogene homolog (avian)

LMX1B

129

3

CDKN2A

33

3

CARD11

17

3

DYSF

18

3

FOXA2 COL18A1 CDX2 SHH CYP2E1 GRIN2A GBX2 IRF4 HIC1 PTPRF MAG

42 75 58 62 22 43 75 19 52 39 14

3 3 3 3 3 3 3 3 3 3 3

SLC6A5

33

3

CHRNE NR2F1 ATOH1 NEUROG3 RARB PCDHGC5

10 23 34 48 5 20

3 3 3 3 3 3

NEDD4L

37

3

ST8SIA1

21

3

MAP2K2 HLA-A TPM1 SLC19A1 PPP1CA TFDP1 HOXD10 PDGFA MEOX2

34 10 33 34 10 27 24 47 11

3 3 3 3 3 3 3 3 3

KCNJ3

22

3

VSX1 SSTR1 NR2F6 PAX3

39 35 22 28

3 3 3 3

LIM homeobox transcription factor 1, beta Cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) Caspase recruitment domain family, member 11 Dysferlin, limb girdle muscular dystrophy 2B (autosomal recessive) Forkhead box A2 Collagen, type XVIII, alpha 1 Caudal type homeobox 2 Sonic hedgehog homolog (Drosophila) Cytochrome P450, family 2, subfamily E, polypeptide 1 Glutamate receptor, ionotropic, N-methyl D-aspartate 2A Gastrulation brain homeobox 2 Interferon regulatory factor 4 Hypermethylated in cancer 1 Protein tyrosine phosphatase, receptor type, F Myelin associated glycoprotein Solute carrier family 6 (neurotransmitter transporter, glycine), member 5 Cholinergic receptor, nicotinic, epsilon Nuclear receptor subfamily 2, group F, member 1 Atonal homolog 1 (Drosophila) Neurogenin 3 Retinoic acid receptor, beta Protocadherin gamma subfamily C, 5 Neural precursor cell expressed, developmentally down-regulated 4-like ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1 Mitogen-activated protein kinase kinase 2 Major histocompatibility complex, class I, A Tropomyosin 1 (alpha) Solute carrier family 19 (folate transporter), member 1 Protein phosphatase 1, catalytic subunit, alpha isoform Transcription factor Dp-1 Homeobox D10 Platelet-derived growth factor alpha polypeptide Mesenchyme homeobox 2 Potassium inwardly-rectifying channel, subfamily J, member 3 Visual system homeobox 1 Somatostatin receptor 1 Nuclear receptor subfamily 2, group F, member 6 Paired box 3

GFRA1 RBP3 HOXC8 KCNIP2 PTK6 LTK WNT5B HOXB7 GHSR

37 6 20 31 11 22 22 23 18

3 3 3 3 3 3 3 3 3

KCNJ2

10

2

MATK NR4A2 PDLIM7 FOXK2

20 60 18 36

2 2 2 2

KCNC1

26

2

CACNA1E

29

2

CNTFR ATP1A1 CSRP1 ZBTB16 CSNK1G2 SHANK1 ZNF217 BMP4 IRS2 CCK ZIC3 MYC PCSK9 DHRS3 BLVRB TOPORS RERE GDNF INPP4B

38 17 14 9 56 62 9 47 33 20 54 42 17 27 12 22 32 41 20

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

MOV10L1

19

2

TACC1 NFIB SORBS1 FZD5

18 35 10 35

2 2 2 2

GDNF family receptor alpha 1 Retinol binding protein 3, interstitial Homeobox C8 Kv channel interacting protein 2 PTK6 protein tyrosine kinase 6 Leukocyte receptor tyrosine kinase Wingless-type MMTV integration site family, member 5B Homeobox B7 Growth hormone secretagogue receptor Potassium inwardly-rectifying channel, subfamily J, member 2 Megakaryocyte-associated tyrosine kinase Nuclear receptor subfamily 4, group A, member 2 PDZ and LIM domain 7 (enigma) Forkhead box K2 Potassium voltage-gated channel, Shaw-related subfamily, member 1 Calcium channel, voltage-dependent, R type, alpha 1E subunit Ciliary neurotrophic factor receptor Atpase, Na+/K+ transporting, alpha 1 polypeptide Cysteine and glycine-rich protein 1 Zinc finger and BTB domain containing 16 Casein kinase 1, gamma 2 SH3 and multiple ankyrin repeat domains 1 Zinc finger protein 217 Bone morphogenetic protein 4 Insulin receptor substrate 2 Cholecystokinin Zic family member 3 (odd-paired homolog, Drosophila) V-myc myelocytomatosis viral oncogene homolog (avian) Proprotein convertase subtilisin/kexin type 9 Dehydrogenase/reductase (SDR family) member 3 Biliverdin reductase B (flavin reductase (NADPH)) Topoisomerase I binding, arginine/serine-rich Arginine-glutamic acid dipeptide (RE) repeats Glial cell derived neurotrophic factor Inositol polyphosphate-4-phosphatase, type II, 105kda Mov10l1, Moloney leukemia virus 10-like 1, homolog (mouse) Transforming, acidic coiled-coil containing protein 1 Nuclear factor I/B Sorbin and SH3 domain containing 1 Frizzled homolog 5 (Drosophila)

JUNB

35

2

SMARCA4

36

2

SLC43A1 COL2A1 IGF1R PIK3R2 FOXF1 TERT SOCS1 P2RX2 MMP17 GRM7 RGS12 JUP HIPK2 FOSB DCHS1 POMC JUN GATA4 SMAD6

29 25 51 35 72 81 24 18 44 16 38 17 12 35 18 19 44 85 10

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

KCNMA1

20

2

UBE2G1

14

2

SOX4 POU3F4 NOS1 ROCK2

39 18 18 12

2 2 2 2

HRK

25

2

INTS6 ATF3 KIAA0020 DSTN ZNF232 PTP4A2 RHEB

14 48 5 14 35 16 16

2 2 2 2 2 2 2

POLR2I

16

2

THRB

20

2

IGFALS

28

2

Jun B proto-oncogene SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 Solute carrier family 43, member 1 Collagen, type II, alpha 1 Insulin-like growth factor 1 receptor Phosphoinositide-3-kinase, regulatory subunit 2 (beta) Forkhead box F1 Telomerase reverse transcriptase Suppressor of cytokine signaling 1 Purinergic receptor P2X, ligand-gated ion channel, 2 Matrix metallopeptidase 17 (membrane-inserted) Glutamate receptor, metabotropic 7 Regulator of G-protein signaling 12 Junction plakoglobin Homeodomain interacting protein kinase 2 FBJ murine osteosarcoma viral oncogene homolog B Dachsous 1 (Drosophila) Proopiomelanocortin Jun oncogene GATA binding protein 4 SMAD family member 6 Potassium large conductance calcium-activated channel, subfamily M, alpha member 1 Ubiquitin-conjugating enzyme E2G 1 (UBC7 homolog, yeast) SRY (sex determining region Y)-box 4 POU class 3 homeobox 4 Nitric oxide synthase 1 (neuronal) Rho-associated, coiled-coil containing protein kinase 2 Harakiri, BCL2 interacting protein (contains only BH3 domain) Integrator complex subunit 6 Activating transcription factor 3 Kiaa0020 Destrin (actin depolymerizing factor) Zinc finger protein 232 Protein tyrosine phosphatase type IVA, member 2 Ras homolog enriched in brain Polymerase (RNA) II (DNA directed) polypeptide I, 14.5kda Thyroid hormone receptor, beta (erythroblastic leukemia viral (v-erb-a) oncogene homolog 2, avian) Insulin-like growth factor binding protein, acid labile

PDXK CUGBP2 GALR1 TBXA2R FADS2 ENAH RGS19

26 21 27 23 22 14 16

2 2 2 2 2 2 2

YWHAZ

25

2

SCHIP1

21

2

KCNB2

7

2

KCNJ9

16

2

ELAVL2

32

2

LTB CHAT ZNF167

8 15 4

2 2 2

SLC16A2

30

2

NEUROD1 CSNK1D S100A6 EOMES

28 49 10 50

2 2 2 2

MFI2

29

2

PLS3 FBN1 SH3GL1 STAT1 EPHB1 EFEMP1 YBX1 STK10 NR3C2 RTN4 EGR4 HTR1A PML DSC3 CHP2 FAM8A1

15 20 13 13 19 9 12 19 30 15 35 18 13 15 11 10

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

subunit Pyridoxal (pyridoxine, vitamin B6) kinase CUG triplet repeat, RNA binding protein 2 Galanin receptor 1 Thromboxane A2 receptor Fatty acid desaturase 2 Enabled homolog (Drosophila) Regulator of G-protein signaling 19 Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide Schwannomin interacting protein 1 Potassium voltage-gated channel, Shab-related subfamily, member 2 Potassium inwardly-rectifying channel, subfamily J, member 9 ELAV (embryonic lethal, abnormal vision, Drosophila)-like 2 (Hu antigen B) Lymphotoxin beta (TNF superfamily, member 3) Choline acetyltransferase Zinc finger protein 167 Solute carrier family 16, member 2 (monocarboxylic acid transporter 8) Neurogenic differentiation 1 Casein kinase 1, delta S100 calcium binding protein A6 Eomesodermin homolog (Xenopus laevis) Antigen p97 (melanoma associated) identified by monoclonal antibodies 133.2 and 96.5 Plastin 3 (T isoform) Fibrillin 1 SH3-domain GRB2-like 1 Signal transducer and activator of transcription 1, 91kda EPH receptor B1 EGF-containing fibulin-like extracellular matrix protein 1 Y box binding protein 1 Serine/threonine kinase 10 Nuclear receptor subfamily 3, group C, member 2 Reticulon 4 Early growth response 4 5-hydroxytryptamine (serotonin) receptor 1A Promyelocytic leukemia Desmocollin 3 Calcineurin B homologous protein 2 Family with sequence similarity 8, member A1

TULP1 TNK1

13 13

2 2

SLC5A5

20

2

ADRA2B VPS4B IL1R2 SYMPK WNT2

14 12 3 14 21

2 2 2 2 2

HSPA5

17

2

LRP8

29

2

NTN1 RAB4A ADK

39 4 13

2 2 2

SMPD3

36

2

KCNK15 MOBP NID2 PAX8 RB1 CD70 RUNX2 ADORA2B ARHGEF1 TTYH1 BRD2

15 6 22 20 26 10 27 19 26 16 33

2 2 2 2 2 2 2 2 2 2 2

MGAT3

39

2

BNIP3L CNOT3 DCC FOXO3 ASCL1 PMP22 TLR2 GPC6 PDK3 RECQL4 TRPS1 E2F3 NTN3

10 12 15 25 31 22 11 15 10 13 15 17 27

2 2 2 2 2 2 2 2 2 2 2 2 2

Tubby like protein 1 Tyrosine kinase, non-receptor, 1 Solute carrier family 5 (sodium iodide symporter), member 5 Adrenergic, alpha-2B-, receptor Vacuolar protein sorting 4 homolog B (S. Cerevisiae) Interleukin 1 receptor, type II Symplekin Wingless-type MMTV integration site family member 2 Heat shock 70kda protein 5 (glucose-regulated protein, 78kda) Low density lipoprotein receptor-related protein 8, apolipoprotein e receptor Netrin 1 RAB4A, member RAS oncogene family Adenosine kinase Sphingomyelin phosphodiesterase 3, neutral membrane (neutral sphingomyelinase II) Potassium channel, subfamily K, member 15 Myelin-associated oligodendrocyte basic protein Nidogen 2 (osteonidogen) Paired box 8 Retinoblastoma 1 CD70 molecule Runt-related transcription factor 2 Adenosine A2b receptor Rho guanine nucleotide exchange factor (GEF) 1 Tweety homolog 1 (Drosophila) Bromodomain containing 2 Mannosyl (beta-1,4-)-glycoprotein beta-1,4-N-acetylglucosaminyltransferase BCL2/adenovirus E1B 19kda interacting protein 3-like CCR4-NOT transcription complex, subunit 3 Deleted in colorectal carcinoma Forkhead box O3 Achaete-scute complex homolog 1 (Drosophila) Peripheral myelin protein 22 Toll-like receptor 2 Glypican 6 Pyruvate dehydrogenase kinase, isozyme 3 Recq protein-like 4 Trichorhinophalangeal syndrome I E2F transcription factor 3 Netrin 3

PTGIS PLXNA3

7 31

2 2

Prostaglandin I2 (prostacyclin) synthase Plexin A3