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Center for Computational Systems Medicine
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Dataset summary

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Drug summary

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Umap of single cell types and conditions (resistant and sensitive)

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Comparison of cell composition between the resistant and sensitive groups (This dataset does not contain this module)

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Comparison of intra-tumor heterogeneity (ITH) and epithelial-mesenchymal transition (EMT) scores of malignant cells between the resistant and sensitive groups

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Difference of cell-cell interactions between the resistant and sensitive groups (This dataset does not contain this module)

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Differentially expressed genes (DEGs) between the resistant and sensitive groups for each cell type

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Mechanism analysis of drug resistance-related DEGs for each cell type in the pre-treatment samples (This dataset does not contain this module)

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Mechanism analysis of drug resistance-related DEGs for each cell type in the post-treatment samples (This dataset does not contain this module)

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Mechanism analysis of drug resistance-related DEGs for each cell type in one patient or cell lines

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MicroRNAs (miRNAs) regulating drug resistance-related DEGs for Malignant cells

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Motifs and transcription factors (TFs) regulating drug resistance-related DEGs for each cell type

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Differentially expressed genes act as transcription factors

Dataset: GSE168668

Dataset summary for GSE168668

Datast informationDatasetGSE168668
PMID34489465
Raw data ID/linkPRJNA713356
OrganismHomo sapiens
SourceLNCaP cell line
TissueCell line
Cancer type level1Prostate cancer
Cancer type level2Prostate cancer
Regimenenzalutamide
Drug typeTargeted therapy
Sample sizeresistant 2, sensitive 1
Cell number10698
Extract protocol10x genomics
Data processingCellRanger 3.0.2
Public datePublic on Aug 17, 2021
DescriptionThis dataset has 1 cell line with 1 sensitive pre-treatment sample and 2 resistant post-treatment samples.

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Drug summary for GSE168668

Drug nameDrugBank IDDrug typeTargets nameTargets uniprot ID
"Enzalutamide"

DB08899

small moleculeARP10275

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Umap of single cell types and conditions (resistant and sensitive)

check buttonUmap of cell types and conditions (resistant and sensitive). If this dataset has both pre-treatment and post-treatment samples, the cell types were annotated together. If this dataset is a cell line dataset, the UMAP of cell clusters and the cell ratio of drug-resistant and sensitive groups within each cluster will also be shown. (If the image exists, the user can click on it to enlarge it in a new window.)
Umap of cell typesboxplotUmap of conditionsboxplot
Umap of cell clustersboxplotCell ratio of drug-resistant and sensitive groups within each clusterboxplot

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Comparison of cell composition between the resistant and sensitive groups

check buttonIn the pre-treatment samples, the cell composition of the resistant and sensitive groups were compared.
* represents significant difference.
(If the image exists, the user can click on it to enlarge it in a new window.)

check buttonIn the post-treatment samples, the cell composition of the resistant and sensitive groups were compared.
* represents significant difference.
(If the image exists, the user can click on it to enlarge it in a new window.)

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Comparison of ITH and EMT scores of malignant cells between the resistant and sensitive groups

check buttonComparison of ITH (intra-tumoral heterogeneity) and EMT (epithelial-mesenchymal transition) scores of malignant cells between the resistant and sensitive groups. ITH represents intratumoral heterogeneity, EMT represents epithelial mesenchymal transition, pre represents pre-treatment, post represents post-treatment, post2 represents longer post-treatment. (If the image exists, the user can click on it to enlarge it in a new window.)
Comparison of ITH scoresboxplotComparison of EMT scoresboxplot

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Difference of cell-cell interactions between the resistant and sensitive groups

check buttonIn the pre-treatment samples, the difference in cell-cell interactions between the resistant and sensitive groups was compared. The numbers indicate the count of cell-cell interactions that were either higher or lower in the resistant group compared to the sensitive group. The dot plots of significant ligand-receptor pairs in the resistant group and sensitive group are subsequently displayed. (If the image exists, the user can click on it to enlarge it in a new window. Complete files can be downloaded from the download section.)

check buttonIn the post-treatment samples, the difference in cell-cell interactions between the resistant and sensitive groups was compared. The numbers indicate the count of cell-cell interactions that were either higher or lower in the resistant group compared to the sensitive group. The dot plots of significant ligand-receptor pairs in the resistant group and sensitive group are subsequently displayed. (If the image exists, the user can click on it to enlarge it in a new window. Complete files can be downloaded from the download section.)

check buttonThis dataset only has one patient or is a cell line dataset, the resistant sample is the post-treatment sample and the sensitive sample is the pre-treatment sample. The difference in cell-cell interactions between the resistant and sensitive groups was compared. The numbers indicate the count of cell-cell interactions that were either higher or lower in the resistant group compared to the sensitive group. The dot plots of significant ligand-receptor pairs in the resistant group and sensitive group are subsequently displayed. (If the image exists, the user can click on it to enlarge it in a new window. Complete files can be downloaded from the download section.)

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Differentially expressed genes (DEGs) between the resistant and sensitive groups for each cell type

check buttonIn the pre-treatment samples, the differentially expressed genes (|avg_log2FC|>0.25 & p_val_adj<0.05) between the resistant and sensitive groups for each cell type.

check buttonIn the post-treatment samples, the differentially expressed genes (|avg_log2FC|>0.25 & p_val_adj<0.05) between the resistant and sensitive groups for each cell type.

check buttonThis dataset only has one patient or is a cell line dataset, the resistant sample is the post-treatment sample and the sensitive sample is the pre-treatment sample. The following are differentially expressed genes (|avg_log2FC|>0.25 & p_val_adj<0.05) between the resistant and sensitive groups for each cell type.
Gene symbolGene idavg_log2FCp_valp_val_adjpct.1pct.2Cell typeTimepoint

GLRX2

ENSG000000235720.2904220.00e+001.96e-440.5260.367Malignant cellsNA

GRB10

ENSG000001060700.2894180.00e+000.00e+000.5220.333Malignant cellsNA

CFL1

ENSG000001727570.2893530.00e+000.00e+000.9990.998Malignant cellsNA

NOL7

ENSG000002259210.2893010.00e+000.00e+000.860.803Malignant cellsNA

MICU2

ENSG000001654870.288170.00e+000.00e+000.4580.293Malignant cellsNA

ANXA7

ENSG000001382790.2881593.50e-446.50e-400.7790.71Malignant cellsNA

ADGRV1

ENSG000001641990.2879421.65e-393.04e-350.3020.172Malignant cellsNA

RRAGA

ENSG000001558760.2878084.04e-407.48e-360.6860.599Malignant cellsNA

HNRNPA3

ENSG000001701440.2870440.00e+000.00e+000.9010.811Malignant cellsNA

UFC1

ENSG000001432220.2863860.00e+009.43e-420.8340.799Malignant cellsNA

SEPT7

NA0.2862960.00e+000.00e+000.8080.701Malignant cellsNA

DDX5

ENSG000001086540.2859320.00e+000.00e+000.9850.958Malignant cellsNA

FUCA2

ENSG000000010360.2856710.00e+000.00e+000.3030.135Malignant cellsNA

PARK7

ENSG000001162880.2855110.00e+000.00e+0011Malignant cellsNA

ATP5PD

ENSG000001678630.2850380.00e+000.00e+000.9640.942Malignant cellsNA

ARF1

ENSG000001437610.2843510.00e+000.00e+000.9490.928Malignant cellsNA

FIBP

ENSG000001725000.2837526.67e-401.23e-350.8750.875Malignant cellsNA

GLOD4

ENSG000001676990.2831154.67e-428.63e-380.5880.464Malignant cellsNA

RNF187

ENSG000002854260.2825490.00e+000.00e+000.9660.903Malignant cellsNA

EIF6

ENSG000002423720.2821431.88e-413.47e-370.7450.685Malignant cellsNA

MRPL13

ENSG000001721720.281245.68e-411.05e-360.7330.653Malignant cellsNA

PSMA7

ENSG000001011820.2803540.00e+000.00e+000.9990.994Malignant cellsNA

LINC01184

NA0.2802740.00e+000.00e+000.40.234Malignant cellsNA

CYC1

ENSG000001790910.2802180.00e+000.00e+000.9670.943Malignant cellsNA

PTTG1IP

ENSG000001832550.2801410.00e+002.66e-420.5090.351Malignant cellsNA

C1orf131

ENSG000001436330.2800759.81e-431.81e-380.5850.453Malignant cellsNA

C6orf203

NA0.2795521.51e-432.80e-390.460.317Malignant cellsNA

FKBP1A

ENSG000000888320.2794534.57e-318.45e-270.740.671Malignant cellsNA

GLYATL1

ENSG000001668400.2793620.00e+008.97e-420.4070.252Malignant cellsNA

NDUFAB1

ENSG000000047790.2789230.00e+000.00e+000.9960.987Malignant cellsNA

PPP2R5A

ENSG000000660270.2786970.00e+000.00e+000.3730.203Malignant cellsNA

NSL1

ENSG000001176970.2786580.00e+005.05e-420.5740.43Malignant cellsNA

KIF5B

ENSG000001707590.2782770.00e+000.00e+000.950.911Malignant cellsNA

SMAP1

ENSG000001123050.2779330.00e+000.00e+000.3890.216Malignant cellsNA

PSMD1

ENSG000001736920.2769728.50e-391.57e-340.6660.567Malignant cellsNA

CLIC1

ENSG000002266510.2760643.98e-427.35e-380.8720.841Malignant cellsNA

YIPF3

ENSG000001372070.2745933.36e-446.19e-400.4820.333Malignant cellsNA

CHD4

ENSG000001116420.2745651.65e-433.05e-390.6720.541Malignant cellsNA

CSNK2B

ENSG000002307000.2737617.54e-431.39e-380.7950.729Malignant cellsNA

NHP2

ENSG000001459120.2733720.00e+000.00e+000.9790.961Malignant cellsNA

TPR

ENSG000000474100.2733460.00e+002.83e-430.8720.813Malignant cellsNA

OLA1

ENSG000001384300.2723950.00e+003.22e-440.8710.83Malignant cellsNA

CSRP1

ENSG000001591760.2722842.09e-423.87e-380.4750.332Malignant cellsNA

RPS26

ENSG000001977280.272110.00e+000.00e+0011Malignant cellsNA

ARID5B

ENSG000001503470.271772.08e-383.84e-340.4890.342Malignant cellsNA

CCDC91

ENSG000001231060.2712465.21e-439.64e-390.4990.353Malignant cellsNA

PRPF4B

ENSG000001127390.2711712.40e-424.44e-380.6250.501Malignant cellsNA

FUBP1

ENSG000001626130.2711022.59e-424.78e-380.4610.313Malignant cellsNA

NADK2

ENSG000001526200.2703727.02e-341.30e-290.4650.34Malignant cellsNA

RETREG1

ENSG000001541530.2699481.40e-452.36e-410.4240.269Malignant cellsNA
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Mechanism analysis of drug resistance-related DEGs for each cell type in the pre-treatment samples

check buttonEnrichment results for 5 known drug-resistant mechanisms in malignant cells and 1 known mechanism in TME cells.The "Signature" column represents the differentially expressed genes (DEGs) used for enrichment. The "Geneset" column represents the genes included in this mechanism. The "Overlap" column represents the number of genes in the "Geneset" that are enriched in the "Signature". The "Enriched Genes" column represents the genes in the "Geneset" that are enriched in the "Signature". (If the image exists, the user can click on it to enlarge it in a new window.)

check buttonHallmark, KEGG and GOBP enrichment results for up-regulated genes in resistant group of pre-treatment samples. Only show the top 50 pathways with fdr<0.05. If certain cell types are not displayed, it means that there are no significant pathways based on DEGs in those cell types. (If the image exists, the user can click on it to enlarge it in a new window. Complete files can be downloaded from the download section.)

check buttonHallmark, KEGG and GOBP enrichment results for down-regulated genes in resistant group of pre-treatment samples. Only show the top 50 pathways with fdr<0.05. If certain cell types are not displayed, it means that there are no significant pathways based on DEGs in those cell types. (If the image exists, the user can click on it to enlarge it in a new window.Complete files can be downloaded from the download section.)

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Mechanism analysis of drug resistance-related DEGs for each cell type in the post-treatment samples

check buttonEnrichment results for 5 known drug resistance mechanisms in malignant cells and 1 known mechanism in TME cells.The "Signature" column represents the differentially expressed genes (DEGs) used for enrichment. The "Geneset" column represents the genes included in this mechanism. The "Overlap" column represents the number of genes in the "Geneset" that are enriched in the "Signature". The "Enriched Genes" column represents the genes in the "Geneset" that are enriched in the "Signature". (If the image exists, the user can click on it to enlarge it in a new window.)

check buttonHallmark, KEGG and GOBP enrichment results for up-regulated genes in resistant group of post-treatment samples. Only show the top 50 pathways with fdr<0.05. If certain cell types are not displayed, it means that there are no significant pathways based on DEGs in those cell types. (If the image exists, the user can click on it to enlarge it in a new window. Complete files can be downloaded from the download section.)

check buttonHallmark, KEGG and GOBP enrichment results for down-regulated genes in resistant group of post-treatment samples. Only show the top 50 pathways with fdr<0.05. If certain cell types are not displayed, it means that there are no significant pathways based on DEGs in those cell types. (If the image exists, the user can click on it to enlarge it in a new window. Complete files can be downloaded from the download section.)

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Mechanism analysis of drug resistance-related DEGs for each cell type in one patient or cell lines

check buttonThis dataset only has one patient or is a cell line dataset, the resistant sample is the post-treatment sample and the sensitive sample is the pre-treatment sample. Enrichment results for 5 known drug resistance mechanisms in malignant cells and 1 known mechanism in TME cells are shown here.The "Signature" column represents the differentially expressed genes (DEGs) used for enrichment. The "Geneset" column represents the genes included in this mechanism. The "Overlap" column represents the number of genes in the "Geneset" that are enriched in the "Signature". The "Enriched Genes" column represents the genes in the "Geneset" that are enriched in the "Signature". (If the image exists, the user can click on it to enlarge it in a new window.)
Enrichment results for 5 known drug resistance mechanisms in malignant cells
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MechnismPvalFDRSignatureGenesetOverlapBackgroundCell typeEnriched Genes
Unusual Activation of Pro-survival Pathway3.30e-131.70e-1212567819323467Malignant cellsPPP2R5A,ADAM10,ADAM9,ADGRV1,BBC3,BRAF,CDK4,CDKN1A,DNMT1,EGFR,FUBP1,HMOX1,JUN,PKM,MAP1LC3B,MYC,PARP1,RALBP1,RPS6,SELENOW,ST3GAL4,SOX4,STMN1,TPD52,TRIM16,ALDH1A3,AR,ATG3,HSPA5,BNIP2,BTG1,CDK1,CCND1,CCNG1,ALCAM,HSPD1,SLC31A1,EHF,EIF3A,HSP90B1,FN1,FOXA1,FTL,FUS,GAPDH,GCLM,GSR,HAX1,HMGN5,HNRNPU,HSPA8,IDH1,EIF4A3,IKBKB,ITGB1,KAT6A,KDM5B,PRKCD,LAMP2,LASP1,LRIG1,MAP1LC3A,NFATC3,NQO1,POMP,PRKDC,PURA,RAP1B,ERBB3,SFPQ,SMC4,SRSF2,TPT1,TMED3,TOP1,TOP2B,USP14,ENO1,FASN,PFKL,SLC16A1,GNAS,CALR,CEBPD,EIF4EBP1,PPP3CA,SQLE,TM7SF2,TNFAIP8,NUPR1,TRIB3,CERS6,ACAT2
Irregularity in Drug Uptake and Drug Efflux4.60e-021.10e-01125637523467Malignant cellsSLC3A2,ABCC1,ABCC4,SLC4A4,SLC7A11
Aberration of the Drug's Therapeutic Target3.50e-015.80e-01125690623467Malignant cellsBRAF,CDK4,EGFR,AR,IDH1,MAOA
Drug Inactivation by Structure Modification7.70e-019.70e-01125627123467Malignant cellsNME1
Epigenetic Alteration of DNA, RNA or Protein1.00e+001.00e+0012564551123467Malignant cellsBRAF,DNMT1,EGFR,PMAIP1,GAPDH,IDH1,SMC4,MALAT1,GDI2,MT-CO2,GABPB1-AS1


check buttonHallmark, KEGG and GOBP enrichment results for up-regulated genes in resistant group. Only show the top 50 pathways with fdr<0.05. If certain cell types are not displayed, it means that there are no significant pathways based on DEGs in those cell types. (If the image exists, the user can click on it to enlarge it in a new window. Complete files can be downloaded from the download section.)
Up-regulated HallmarkUp-regulated KEGGUp-regulated GO BP

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check buttonHallmark, KEGG and GOBP enrichment results for down-regulated genes in resistant group. Only show the top 50 pathways with fdr<0.05. If certain cell types are not displayed, it means that there are no significant pathways based on DEGs in those cell types. (If the image exists, the user can click on it to enlarge it in a new window. Complete files can be downloaded from the download section.)
Down-regulated HallmarkDown-regulated KEGGDown-regulated GO BP

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MicroRNAs (miRNAs) regulating drug resistance-related DEGs for malignant cells

check buttonIn the pre-treatment samples, the miRNAs with a score greater than 80 that regulate the top10 abs(avg_log2FC) drug resistance-related DEGs for malignant cells are shown here. If the gene does not have any miRNAs with a score greater than 80, it will not be shown. Here only the names of miRNAs with a score greater than 90 are shown, but some names will not be shown because of too many overlaps. (Complete files containing all datasets and cell types can be downloaded from the download section.)

check buttonIn the post-treatment samples, the miRNAs with a score greater than 80 that regulate the top10 abs(avg_log2FC) drug resistance-related DEGs for Malignant cells are shown here. If the gene does not have any miRNAs with a score greater than 80, it will not be shown. Here only the names of miRNAs with a score greater than 90 are shown, but some names will not be shown because of too many overlaps. (Complete files containing all datasets and cell types can be downloaded from the download section.)

check buttonThis dataset only has one patient or is a cell line dataset, the resistant sample is the post-treatment sample and the sensitive sample is the pre-treatment sample. The miRNAs with a score greater than 80 that regulate the top10 abs(avg_log2FC) drug resistance-related DEGs for Malignant cells are shown here. Here only the names of miRNAs with a score greater than 80 are shown, but some names will not be shown because of too many overlaps. If the gene does not have any miRNAs with a score greater than 90, it will not be shown. (Complete files containing all datasets and cell types can be downloaded from the download section.)
Regulating up-regulated DEGs in resistant groupRegulating down-regulated DEGs in resistant group
boxplotboxplot

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Motifs and transcription factors (TFs) regulating drug resistance-related DEGs for each cell type

check buttonIn the pre-treatment samples, the motifs and TFs that regulate drug resistance-related DEGs for each cell type are shown here. (Complete files can be downloaded from the download section.)

check buttonIn the post-treatment samples, the motifs and TFs that regulate drug resistance-related DEGs for each cell type are shown here. (Complete files can be downloaded from the download section.)

check buttonThis dataset only has one patient or is a cell line dataset, the resistant sample is the post-treatment sample and the sensitive sample is the pre-treatment sample. Motifs and TFs that regulate drug resistance-related DEGs for each cell type are shown here. (Complete files can be downloaded from the download section.)
Motifs and TFs regulating up-regulated DEGs in resistant group
motifmotifNESAUCTF_highConfCell_type
motifmetacluster_174.34.490.054MBD2; NFYA; NFYB; NFYC; PBX3 (directAnnotation). Malignant cells
motiftransfac_pro__M059814.260.0525ZNF233 (directAnnotation). Malignant cells
motifmetacluster_57.34.250.0525ARNT; ATF3; ATF3; ATF3; ATF3; BHLHE40; BHLHE40; BHLHE40; BHLHE41; BHLHE41; BHLHE41; MITF; MITF; MITF; MLX; MLXIPL; SREBF1; SREBF1; SREBF1; SREBF1; SREBF2; SREBF2; SREBF2; TFE3; TFEC; USF1; USF1; USF1; USF1; USF1; USF1; USF1; USF1; USF1; USF2; USF2; USF2; USF2; USF2; USF2; USF2; USF2; USF2; USF2; USF2; USF2; USF2; ZNF507 (directAnnotation). ARNTL; BHLHE40; BHLHE40; BHLHE41; HELT; HES1; HES2; HES3; HES5; HES6; HES7; HEY1; HEY2; HEYL; MLX; MLX; SREBF1; SREBF2; TFE3; USF1; USF1; USF2; USF2 (inferredBy_Orthology). Malignant cells
motifjaspar__MA0502.24.070.0513NFYB (directAnnotation). Malignant cells
motiftaipale_tf_pairs__E2F1_ELK1_SGCGCNNNNNCGGAAGN_CAP_repr4.040.0512E2F1; ELK1 (directAnnotation). Malignant cells
motifdbtfbs__E4F1_K562_ENCSR731LHZ_merged_N13.910.0504E4F1 (directAnnotation). Malignant cells
motifmetacluster_174.23.80.0497CEBPZ; CEBPZ; DRAP1; FOS; FOXI1; FOXI1; HMGXB3; IRF3; NFYA; NFYA; NFYA; NFYA; NFYA; NFYA; NFYA; NFYA; NFYA; NFYB; NFYB; NFYB; NFYB; NFYB; NFYC; NFYC; NFYC; NFYC; NFYC; NFYC; NFYC; PBX3; PBX3; SP2 (directAnnotation). NFYA; NFYA; NFYC; PBX1; PBX3 (inferredBy_Orthology). Malignant cells
motiftransfac_pro__M049503.770.0495EGR1 (directAnnotation). Malignant cells
motiftaipale_tf_pairs__ETV2_HES7_RSCGGAANNNNNNNCACGTGNN_CAP_repr3.760.0494ETV2; HES7 (directAnnotation). Malignant cells
motiftaipale_tf_pairs__GCM1_ETV4_RTGCGGGCGGAAGTR_CAP3.730.0492ETV4; GCM1 (directAnnotation). Malignant cells
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Motifs and TFs regulating down-regulated DEGs in resistant group
motifmotifNESAUCTF_highConfCell_type
motifkznf__ZBTB14_Schmitges2016_RCADE3.730.0664ZBTB14 (directAnnotation). Malignant cells
motiftaipale_tf_pairs__E2F3_HES7_NNNNGCGCSNNNNNCACGTGNN_CAP3.640.0656E2F3; HES7 (directAnnotation). Malignant cells
motiftransfac_pro__M020893.510.0644E2F3 (directAnnotation). Malignant cells
motiftaipale_cyt_meth__E2F2_NCGCGCGCGCM_eDBD_meth3.480.0642E2F2 (directAnnotation). Malignant cells
motiftransfac_pro__M008033.470.0641E2F1; E2F3; E2F4; TFDP1 (directAnnotation). Malignant cells
motiftransfac_pro__M048173.250.0621ZBTB33 (directAnnotation). Malignant cells
motifmetacluster_143.133.190.0615ZBTB7A (directAnnotation). Malignant cells
motiftransfac_pro__M028613.170.0614GATA6 (inferredBy_Orthology). Malignant cells
motiftfdimers__MD004833.170.0614ZBTB14 (directAnnotation). Malignant cells
motifcisbp__M079383.160.0613E2F1 (directAnnotation). Malignant cells
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Differentially expressed genes act as transcription factors

check buttonThis table shows the differentially expressed genes that act as transcription factors. (Complete files can be downloaded from the download section.)
TFmotifExpressionCell typeTimepoint

HES1

metacluster_57.3upMalignant cellsNA

TFDP1

transfac_pro__M00803downMalignant cellsNA

SMAD9

jaspar__MA0535.1downMalignant cellsNA

TFDP1

metacluster_15.2downMalignant cellsNA

TFDP1

jaspar__MA1122.1downMalignant cellsNA

ATF3

metacluster_57.3downMalignant cellsNA

HES6

metacluster_57.3downMalignant cellsNA

ZNF814

transfac_pro__M06071downMalignant cellsNA

ELK4

metacluster_166.2downMalignant cellsNA

ETV1

metacluster_166.2downMalignant cellsNA
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1"Sun X, Zhang Y, Li H, Zhou Y, Shi S, Chen Z, He X, Zhang H, Li F, Yin J, Mou M, Wang Y, Qiu Y, Zhu F. DRESIS: the first comprehensive landscape of drug resistance information. Nucleic Acids Res. 2023 Jan 6;51(D1):D1263-D1275. doi: 10.1093/nar/gkac812. PMID: 36243960; PMCID: PMC9825618."
2"Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037. PMID: 29126136; PMCID: PMC5753335."