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200214 WT1 Paper Nat Med SE1[2] Supplementary Fig. 1 a c Control PBS WT1 KD ADR Nphs2-2 Synpo-1 Nphs2-2 Synpo-1 100 100 **** 150 250 **** **** **** 80 **** 80 200 100 60 60 **** 150 **** **** 40 100 40 **** **** 50 ** ** ** * ** ** 20 20 50 * **** Relative Enrichment Relative Relative Enrichment 0 0 0 0 H4K8Ac H3K9m3 H4K8Ac H4K8Ac H3K9m3 H4K8Ac H3K9m3 H3K4me3 H4K12Ac H4K12Ac H3K9m3 H3K4me3 H4K12Ac H3K4me3 H4K12Ac H3K4me3 H3K27me3 H3K27me3 b d ** ** *** * 60 25 50 30 20 40 40 20 15 30 10 20 20 10 Enrichment 5 Enrichment 10 WT1 Relative Relative WT1 Relative WT1 0 0 0 0 Control WT1 KD Control WT1 KD PBS ADR PBS ADR Supplementary Fig. 1. WT1 controls chromatin remodeling at Nphs2 and Synpo genes in murine immortalized podocytes (a, c) Histones direct ChIP-qPCR using active histones marks (H3K4m3, H4K8ac) and repressive histones marks (H3K9me3 and H3K27me3) at Nphs2-2 and Synpo-1 peaks from immortalized mouse podocytes treated with PBS or 1µg/mL of ADR during 16 hours (a) or podocytes transfected with siRNA scramble or siRNA WT1 (c). **** P<0.0001, *** P<0.001, ** P<0.01, * P<0.05 (Multiple t-test with FDR determined using the two-stage linear step-up procedure of Benjamini, Krieger and Yekutieli) compared to control. (b, d) WT1 direct ChIP-qPCR at Nphs2-2 and Synpo-1 peaks from immortalized mouse podocytes treated with PBS or 1µg/mL of ADR during 16 hours at Nphs2-2 and Synpo-1 peaks (b) or podocytes transfected with siRNA scramble or siRNA WT1 (d). Bars represent means and error bars ± SEMs. *** P<0.001; **P<0.01; *P<0.05 (n=3). 39 Supplementary Fig. 2 a PBS b Wt1 Nphs2 Synpo BALB/cJ ADR 800 5 * 80 15 ** * *** ** ** *** ** * ** 600 4 60 ** ** 10 3 400 GAPDH 40 ratio 2 ** 5 20 BALB/cJ 1 200 *** Normalized Gene/ 0 0 0 PBS D3 D4 D5 D6 D7 PBS D3 D4 D5 D6 D7 PBS D3 D4 D5 D6 D7 Albumin/creatinine(mg/g) 0 D0 D3 D4 D5 D7 c Saline D3 D5 D7 WT1 BALB/cJ Merge Nphs2 Synpo d 24kb 33kb [0-300] [0-300] seq - WT1 WT1 ChIP Nphs2-1 Nphs2-2 Nphs2-3 Synpo-1 Synpo-2 Synpo-3 Nphs2-1 Nphs2-2 Nphs2-3 Synpo-1 Synpo-2 Synpo-3 40 30 80 20 40 50 * * **** *** * * ** ** ** **** 30 * 40 60 **** 15 30 20 30 40 10 20 20 WT1 20 10 Relative Relative 10 20 5 10 10 Enrichment 0 0 0 0 0 0 PBS D3 D4 D5 D6 D7 PBS D3 D4 D5 D6 D7 PBS D3 D4 D5 D6 D7 PBS D3 D4 D5 D6 D7 PBS D3 D4 D5 D6 D7 PBS D3 D4 D5 D6 D7 Supplementary Fig. 2. Transient increase in the expression of key podocyte genes in ADR-injured BALB/cJ mice (a) Quantification of albumin/creatinine level during the course of ADR injury from BALB/cJ mice injected with 10.5mg/kg of ADR (grey bars) or PBS (black bars). Bars represent means and error bars ± SEMs. ***P<0.001; **P<0.01 (n=3 replicates). (b) RT-qPCR of Wt1, Nphs2 and Synpo from isolated glomeruli from BALB/cJ during injury. One-way ANOVA with Tukey’s multiple comparisons test were used. ***P<0.001; **P<0.01; *P<0.05 (n=3 replicates). (c) Immunofluorescent staining of WT1 (red) in BALB/cJ mice in glomeruli. Scale bar 50µM. (d) Upper panels representing IGV plots of Nphs2 and Synpo genes for WT1 ChIP-seq showing WT1 binding sites (gray highlighted boxes) in uninjured podocytes: Nphs2-1, Nphs2-2, Nphs2-3, Synpo-1, Synpo-2 and Synpo-3. Lower panels: WT1 dynamic binding at Nphs2 and Synpo genes measured by WT1 direct ChIP-qPCR from isolated glomeruli from BALB/cJ mice (n=3). ANOVA with Tukey’s multiple comparisons test were used. **** P<0.001; ***P<0.001; **P<0.01; *P<0.05. 40 Supplementary Fig. 3 a WT1 bound genes with new binding sites at D9 b New WT1 bound genes at D9 22kb 77kb [0-200] [0-200] PBS PBS [0-200] [0-200] D9 D9 [0-200] [0-200] D14 D14 Rhpn1 Kdr 77kb 25kb [0-400] [0-200] PBS PBS [0-400] [0-200] D9 D9 [0-400] [0-200] D14 D14 Ildr2 Cryab 205kb 88kb [0-200] [0-200] PBS PBS [0-200] [0-200] D9 D9 [0-200] [0-200] D14 D14 Zhx2 Itga6 Supplementary Fig. 3. Identification of new WT1 bound sites at the onset of proteinuria in mTmG-Nphs2cre mice (a and b) Identification of new WT1 binding sites at D9 within genes that were already bound (a) or unbound (b) in uninjured podocytes. WT1 ChIP-seq IGV plots of Rhpn1, Ildr2 and Zhx2 genes (a) or Kdr, Cryab and Itga6 genes (b) showing WT1 binding sites during injury (uninjured/PBS: blue, D9: orange, D14: red). Red arrows show TSSs and transcription direction. Green arrows show new WT1 binding sites present at D9. 41 Supplementary fig 4 15546 Percent (%) a 15000 13459 b c Percent (%) 0 20 40 60 80 100 10000 0 20 40 60 80 100 promoter PBS codingExon (n=29,005) intron Up ADR 5000 PBS (n=2,485) Intersection size 2890 5'UTR 3'UTR 0 ADR intergenic Up Down 16,349 ADR 29,005 PBS Down ADR (n=14,109) 30000 0 WT1 binding changes Number of peaks d f 2500 Increased WT1 binding at ADR class1 class1 negative regulation of phosphorylation(63) ● negative regulation of protein phosphorylation(60) ● negative regulation of phosphate metabolic process(68) ● class2 negative regulation of protein metabolic process(95) ● class2 regulation of cytokine production(94) ● logP negative regulation of protein modification process(67) ● 25 class3 negative regulation of cellular protein metabolic process(82) ● ● class3 cell junction organization(37) 20 class4 intrinsic apoptotic signaling pathway in response to DNA damage(25) ● apoptotic signaling pathway(55) ● 15 Genes class4 positive regulation of cell death(79) ● negative regulation of kinase activity(42) ● negative regulation of protein kinase activity(40) ● negative regulation of transferase activity(43) ● cell junction assembly(26) ● cellular response to organonitrogen compound(70) ● Unbound modulation by virus of host morphology or physiology(14) ● Unbound intrinsic apoptotic signaling pathway(36) ● actin cytoskeleton organization(83) ● cell−cell junction organization(31) ● Decreased WT1 binding at ADR 0 paraxial mesoderm development(14) ● g ● PBS ADR paraxial mesoderm morphogenesis(9) glomerulus development(37) ● class1 class4 regulation of cell shape(58) ● mesoderm development(61) ● logP class2 Unbound organ growth(26) ● class3 lymph vessel morphogenesis(10) ● 60 cell−cell junction organization(62) ● 50 glomerular visceral epithelial cell differentiation(14) ● insulin receptor signaling pathway(33) ● 40 ● glomerular epithelial cell differentiation(14) 30 e cell junction organization(68) ● epithelial cell differentiation involved in kidney development(19) ● cellular response to peptide hormone stimulus(67) ● muscle cell proliferation(14) ● Percent (%) transforming growth factor beta receptor signaling pathway(44) ● ● 0 20 40 60 80 100 cardiac muscle cell proliferation(13) lymphangiogenesis(9) ● embryonic cranial skeleton morphogenesis(27) ● n=23968 Background cellular response to insulin stimulus(53) ● Up ADR n=1816 Up Down Down ADR n=5248 Genes with differential WT1 binding (Class defined in uninjured state) Supplementary Fig. 4. Dynamics of WT1 binding during the injury response in BALB/cJ mice (a) Number of WT1 binding sites in control and after ADR. Grey bars represent the number of peaks common to each condition. Blue bar plot shows total binding site number. (b and c) Genomic distribution of (b) all WT1 binding sites or (c) WT1 binding sites that significantly changed during injury. (d) Alluvial diagram showing gene class changes after injury: class 1 (pink), class 2 (blue), class 3 (green), class 4 (purple) and unbound class (orange). Y-axis represents the number of genes per class, and X-axis the injury time points. (e) Proportion of each gene class for the genes associated with significant changes in WT1 binding intensity after ADR injury. Gene classes are based on the WT1 binding status in uninjured podocytes. Background indicates the distribution of gene classes for all bound genes (green). White represents unbound genes. The number on the top of the last two columns represents the number of genes with WT1 binding sites that significantly changed during the course of injury. (f) GO terms representing genes at which WT1 binding increased after ADR (upper panel) or decreased (lower panel). 42 Supplementary Fig. 5 a promoter intron 3'UTR c 8 codingExon 5'UTR intergenic 6 Percent (%) 0 20 40 60 80 100 4 Genome PBS n=23,163 2 D9 n=31,639 D14 n=6,567 Expression level (Log2 FPKM+1) 0 PBS D9 b Percent (%) 0 20 40 60 80 100 Differentially expressed genes PBS d Up n=6,243 significant WT1 binding changes no significant WT1 binding changes D9 Up 93% Down Down n=468 D9 D14 Up n=93 38.6% D14 Up Down 99% 64.3% WT1 binding changes Down n=17,440 Supplementary Fig. 5. Effect of ADR on WT1 binding and gene expression in in mTmG-Nphs2cre mice (a and b) Genomic distribution of all WT1 binding sites (a) or WT1 binding sites that significantly changed during injury (b). (c) Expression levels of the 223 genes with more than 2 fold increase of expression at D9 compared to control. The majority of genes were silent in uninjured podocytes. (d) Portions of differentially expressed genes with significant changes in WT1 binding at D9 (38.6%) and D14 (64.3%). 43 E E paraxial mesoderm development(14) paraxial mesoderm morphogenesis(9) glomerulus development(37) paraxial mesoderm development(14) regulation of cell shape(58) logP paraxial mesoderm morphogenesis(9) mesoderm development(61) glomerulus development(37) ADR down BALB/C organ growth(26) regulation of cell shape(58) lymph vessel morphogenesis(10) logP mesoderm development(61) 60 ADR down BALB/C organ growth(26) glomerular visceral epithelial cell differentiation(14) lymph vessel morphogenesis(10) 50 insulin receptor signaling pathway(33) glomerular epithelial cell differentiation(14) 60 40 glomerular visceral epithelial cell differentiation(14) cell junction organization(68) insulin receptor signaling pathway(33) 5030 epithelial cell differentiation involved in kidney development(19) glomerular epithelial cell differentiation(14) cellular response to peptide hormone stimulus(67) 40 cell junction organization(68) muscle cell proliferation(14) epithelial cell differentiation involved in kidney development(19) Supplementary30 transforming growth factor beta Fig.
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