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Supplementary Figure 1 6XSSOHPHQWDU\)LJXUH CCLE B FLI1 ChIP-Seq A 3 FRPPRQ 40 (ZLQJ6SHFLILF 2 A673 6.10& 477 Q 690 30 0 UHSHDWV Q Q A 20 í Q 57226 RI**$ ORJ)3.0LQRWKHUFDQFHUV í í A673 6.10& 06& RYHUODS í 0 23 06& ORJ)3.0LQ(ZLQJ6DUFRPD SHDNV SHDNV SHDNV SHDNV & ./) 67($3 (:6)/,ERXQG 3'(% ! **$AUHSHDWV 3335$ ABI3 '1$-& '863 13<5 .&1( 5%0 DOO**$AUHSHDWUHJLRQV 1.; NEDURXQGWKH766 9$9 ;* .&1$% 4 .&1$ 51) 0<20 3 355/ 355T4 &'$ $'5% 2 '&'& 711, 8*7$ 3+263+2 )(=) *1*7 ORJ QXPEHURIUHSHDWV A571 0 13<5 /2;+' /,3, 5$; 0 40 60 20 GLVWDQFHIURP766 NE D TCGA 35$0( 5 code cancer normal tumor LAML Acute Myeloid Leukemia 0 151 ORJ )3.0 ACC AdrenocoƌƟcal carcinoma 0 79 0 BLCA Bladder Urothelial Carcinoma 19 411 LGG Brain Lower Grade Glioma 0 529 COAD Colon adenocarcinoma 41 464 5%0 ESCA Esophageal carcinoma 11 162 GBM Glioblastoma muůƟforme 5 168 5 KICH Kidney Chromophobe 24 65 KIRP Kidney renal papillary cell carcinoma 32 289 LIHC Liver hepatocellular carcinoma 50 374 ORJ )3.0 LUAD Lung adenocarcinoma 59 526 0 LUSC Lung squamous cell carcinoma 49 501 DLBC Lymphoid Neoplasm Diīuse Large B-cell Lym 042 /,3, MESO Mesothelioma 0 1 OV Ovarian serous cystadenocarcinoma 0 379 PAAD PancreĂƟc adenocarcinoma 4 178 5 PCPG Pheochromocytoma and Paraganglioma 3 150 PRAD Prostate adenocarcinoma 52 499 READ Rectum adenocarcinoma 1 6 ORJ )3.0 SARC Sarcoma 0 35 0 SKCM Skin Cutaneous Melanoma 1 471 STAD Stomach adenocarcinoma 32 375 /2;+' WXPRU TGCT dĞƐƟĐƵůĂƌ'ĞƌŵĞůůdƵŵŽƌƐ 0156 THCA Thyroid carcinoma 58 510 QRUPDO UCS Uterine Carcinosarcoma 0 56 5 ORJ )3.0 0 / / 29 $&& 8&6 /** *%0 /,+& .,53 .,5& .,&+ %/&$ /$0 67$' LUAD '/%& /86& 7*&7 7+&$ 3$$' (6&$ &(6& 35$' 6$5& &+2 5($' %5&$ 8&(& 3&3* 6.&0 &2$' 0(62 Supplementary Figure1(contd) #samples G GLG1 BCL11B NKX2-2 PAX7 CD99 RBM11 LIPI LOXHD1 % non-EWS samples E Ewings Sarcoma 10 10 10 10 10 10 10 10 0 0 0 0 0 0 0 0 + EwS MET500 (n=507) with > EWS median expression pan cancer 11 í Ewings Sarcoma 496 10 20 30 40 50 60 0 (n=980) pan cancer CCLE PRRT4 RNF182 MYOM2 9 GNGT2 KCNAB3 DUSP26 971 NPY5R Adipose - Visceral (Omentum) Brain - Caudate (basal ganglia)Testis Brain - Putamen (basal ganglia)Pituitary KCNA2 Whole Blood 172 RAX ESS32 genes(FPKM) 103 0 100 200 Median expressionof 393 PDE1B FEZF1 227 TNNI3 KLF1 MET500 +EwS Brain - Nucleus accumbensAdipose (basal - Subcutaneous ganglia) CD79A PRR5L ABI3 117 ARTN Breast - Mammary Tissue VAV1 STEAP2 Lung 97 DCDC2 Spleen ADRB3 320 XG 5 104 PHOSPHO1 Brain - Frontal CortexBrain - (BA9) Cortex 350 DNAJC12 214 NPY1R 114 PPP1R1A Heart - Left Ventricle 113 Brain - Anterior cingulate cortex (BA24) Skin - SunHeart Exposed - Atrial Appendage(LowerThyroid leg) Kidney - Cortex 108 NKX2-2 323 UGT3A2 218 32 194 GTEX V6p(n=11401) Brain - FallopianHippocampus Tube 357 LOXHD1 RBM11 Brain - Cerebellar Hemisphere 84 Brain - Cerebellum 6 Small Intestine - Terminal Ileum Skin - Not Sun Exposed (Suprapubic)Ovary 94 Artery - Coronary 97 LIPI 125 Esophagus - Gastroesophageal Junction 105 Brain - Amygdala 133 88 Esophagus - Muscularis 250 Stomach F 72 PHOSPHO1 193 Colon - Sigmoid PPP1R1A DNAJC12 KCNAB3 LOXHD1 DUSP26 UGT3A2 STEAP2 RNF182 MYOM2 NKX2-2 153 GNGT2 DCDC2 NPY5R KCNA2 ADRB3 KCNE3 NPY1R PDE1B PRRT4 RBM11 CD79A PRR5L FEZF1 Minor Salivary Gland KLF15 TNNI3 ARTN VAV1 Pancreas 247 ABI3 LIPI XG Brain Muscle- Hypothalamus - Skeletal 149 171 57 Testis Nerve - Tibial Pituitary Colon - Transverse 430 Whole Blood 96 EsophagusArtery - Mucosa - Aorta Adipose - Visceral (Omentum) 304 Brain - Caudate (basal ganglia) 196 Brain - Putamen (basal ganglia) Artery - Tibial 224 Lung Spleen 286 Bladder Adipose - Subcutaneous 332 Breast - Mammary Tissue Cervix - EctocervixVagina 11 Brain - Cortex Uterus 96 Brain - Nucleus accumbens (basal ganglia) 83 Brain - Frontal Cortex (BA9) Brain - Spinal cord (cervicalAdrenalProstate c-1)Gland Thyroid Brain - Substantia nigra 6 Heart - Left Ventricle 106 Kidney - Cortex Liver 145 Heart - Atrial Appendage Cervix - Endocervix 119 Skin - Sun Exposed (Lower leg) 63 Brain - Anterior cingulate cortex (BA24) Fallopian Tube 71 Brain - Hippocampus 5 Ovary Brain - Cerebellum H Brain - Cerebellar Hemisphere Artery - Coronary I Small Intestine - Terminal Ileum GTEx Normal Skeletal Muscle Skin - Not Sun Exposed (Suprapubic) LOXHD1 mRNA expression LOXHD1 (log2 _ z-score) Brain - Amygdala Stomach 1e4 1e3 1e2 0.1 10 Esophagus - Gastroesophageal Junction 1 Esophagus - Muscularis ( N = 18) Colon - Sigmoid non-EwS Pancreas (n=4) Minor Salivary Gland Muscle - Skeletal Brain - Hypothalamus p <0.01 Nerve - Tibial Colon - Transverse Artery - Aorta * Primary Esophagus - Mucosa (n=12) ( N = 64) EwS Artery - Tibial qRT-PCR Bladder Vagina Uterus Cervix - Ectocervix Metastasis Prostate ( N = 14) Adrenal Gland HeLA RD-ES Liver Brain - Substantia nigra Brain - Spinal cord (cervical c-1) Cervix - Endocervix Recurrence ( N = 10) 0.0 0.2 0.4 0.6 0.8 1.0 FPKM Supplementary Figure 1: Integrative analysis of ChIP-seq and CCLE, MET500, TCGA and GTEx transcriptomic datasets. (A) Analysis of CCLE dataset; Expression of the 516 genes (step 1 of Fig. 1a) in EwS vs other cell lines. The 89 EwS specific genes, seen in the lower-right quadrant and encircled, are expressed only in EwS cell lines and show <1 FPKM expression in all others. (B) Analysis of FLI1-ChIP-seq data; (left) Overlap analysis between FLI1 enriched ChIP-Seq peaks in A673 (GSM1517562), SK-NM-C (GSM1517537), and EWSR1-FLI1 overexpressed MSCs (GSM2472088, GSM2472102, GSM2472108) yields 1473 conserved FLI1-bound regions, (right) distribution of the number of GGAA microsatellite repeats contained within A673-specific, SK-N-MC-specific, MSC-specific and the 1473 overlapping regions shows pronounced enrichment of the GGAA microsatellites in the overlapping regions. (C) Colormap shows the locations of GGAA microsatellite repeat regions േͳͲͲ kb around the TSS of the ESS32 genes. Symbol overlays represent regions with >= 5 GGAA repeats (blue circles) and contain a FLI1 ChIP-seq enrichment peak (red diamonds). (D) Analysis of TCGA dataset; Boxplot showing nearly zero expression of LOXHD1 and LIPI in all TCGA cancer-subtypes in tumor and normal samples. The expression of RBM11 located in LIPI locus is shown. Expression of PRAME is shown as an example of gene that is expressed across all cancer-subtypes. Abbreviation of codes for cancer- subtypes and the corresponding numbers of normal and tumor samples are shown alongside. (E) Analysis of MET500 RNA-seq dataset; Plot showing the median expression of the ESS32 genes (step 3 in Fig. 1a) in EwS against the percentage of non-Ewing samples that show expression higher than the median value in EwS. The dotted line marks the cutoff of 1%. (F) Analysis of GTEx datasets; Heatmap showing the expression of the ESS32 genes showing null expression of LOXHD1, LIPI in all tissues except testis. (G) Box plots comparing the expressions of indicated targets across MET500 + EwS (n=507), CCLE (n= 980), and GTEX (n=11401) samples. (H) Box plots showing LOXHD1 expression in the indicated samples. Publicly available Affymetrix dataset GSE34620 comprising 117 EwS samples was analyzed and Log2 z-score is plotted. p <0.01 One-way Anova between the groups. (I) qRT-PCR analysis of LOXHD1 mRNA expression in an independent cohort of EwS tumor tissues, non-EwS tissues (testis is indicated with orange border), HeLa and RD-ES cells were used as negative and positive control, respectively. * p < 0.001, by two-tailed Student’s t test. Supplementary Figure 2 A B coiled-coil prediction 1.0 0.8 0.6 0.4 t14 score 0.2 0.0 0 200 400 600 800 1000 1200 1400 1600 1800 2000 Amino acid C LOXHD1- NLS coiled coil domain NLS coiled coil HA anti-HA DAPI Merge 10 μm Supplementary Figure 2: Domain prediction of LOXHD1 protein, and the effect of LOXHD1 overexpression in Hela cells. (A) Coiled-coil structure prediction by COILS (https://embnet.vital- it.ch/software/COILS_form.html), y-axis shows the probability of a 14 amino acid (aa) coiled-coil structure and the x-axis shows the amino acids position of LOXHD1 protein. The predicted coil- coil structure is seen as the peak between aa 653 to aa 677. (B) Nuclear localization signals (NLS) predicted by cNLS Mapper (http://nls-mapper.iab.keio.ac.jp/cgi-bin/NLS_Mapper_form.cgi), NLS with a score larger than 8 is exclusively localized to the nucleus. (C) Functional validation of NLS. Immunofluorescence staining with HA antibody showing nuclear signal in HEK293T cells transfected with plasmid containing HA-tagged NLS-coiled-coil domain of LOXHD1. Supplementary Figure 3 A B shNT shFLI1 shERG 1.2 1.2 GSE31215 GSE94277 1 1 8 6 0.8 0.8 6 5 expression 0.6 4 expression 0.6 FLI1 4 2 0.4 ERG 0.4 0 Fold Fold LOXHD1 expression (a.u) 0.2 0.2 1 LOXHD1 expression (FPKM) 1 EV EV FLI1 0 0 EWS-FLI EWS-FLI MSC MSC RD-ES CHLA-10 SK-N-MC CADO-ES 5 kb C hg19, chr21:15,577,038-15,592,092 [0-60] FLI1 MSC [0-25] H3K27ac [0-60] FLI1 [0-25] H3K27ac MSC + EWS-FLI1 FLI1 H3K27ac SK-N-MC H3K4me3 ESS32 enhancer layered H3K27ac from encode --(11 GGAA)-- LIPI RBM11 Supplementary Figure 3: LOXHD1 expression in EWSR1-FLI1 overexpressing MSCs and FLI knockdown EwS cell lines. (A) (left) Comparison of LOXHD1 expression profiled using Affymetrix Human Genome U133 Plus 2.0 Array (GSE31215) in MSCs expressing EWSR1-FLI1 (n=4), (right) Comparison of LOXHD1 FPKM expression in MSCs expressing EWSR1-FLI1 (n=4) and wild type FLI1 (n=4), profiled using RNA-seq (GSE94277). (B) Bar graph showing qRT- PCR results of FLI1 (left) and ERG (right) expression with shRNA knockdown of EWSR1-FLI1 and EWSR1-ERG respectively in the indicated EwS cells.
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