Dissecting the DNA binding landscape and gene regulatory network of p63 and p53
- Computational Biology Group, Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), Germany
- Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Germany
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, United Kingdom
Figures
Figure 1
Meta-analysis of p63-dependent gene regulation.
(A) Distribution of the number of genes found in each of the p63 Expression Score groups. Because p63 Expression Score group ‘14’ and ‘−12’ contained only two genes they were included in group ‘13’ …
Figure 2
Gene sets enriched among genes commonly regulated by p63.
Enrichment of (A, B, C, E) MSigDB gene sets or (D) genes up- and down-regulated across squamous cell cancers (SCC) (Cancer Genome Atlas Research Network et al., 2018) among genes ranked by the p63 …
Figure 3
Transcription factors in the p63 GRN.
(A) Significant (adj.p-value≤0.05) enrichment of TF binding at genes with a p63 Expression Score ≥8 (green) or ≤ −8 (red) as identified by Enrichr (Kuleshov et al., 2016). (B) Enrichment of MSigDB …
Figure 4
p63 and p53 regulate largely distinct target gene sets.
(A) The p63 Expression Score compared to the previously published p53 Expression Score that was generated using the same meta-analysis approach (Fischer et al., 2016a) for all 16,198 genes for which …
Figure 5 with 4 supplements
The p63 and p53 DNA-binding landscape.
(A and B) The number of p63 and p53 binding peaks sorted by the number of datasets that commonly identified/support the peak. (C) The number of p53 and p63 peaks identified in the 28 p53 and 20 p63 …
Figure 5—figure supplement 1
Correlation between p53 and p63 binding frequency and motif consensus.
(A and B) Correlation between dataset support for p53 and p63 binding. (C to F) Correlation between HOMER motif score for primary and secondary ‘p53+p63’ motifs and dataset support for (C and D) p53 …
Figure 5—figure supplement 2
Correlation between p53 and p63 binding frequency and motif consensus.
Correlation between HOMER motif score for primary, secondary, and tertiary (A to C) ‘p53’ motifs or (D to F) ‘p63’ motifs and dataset support for (A to C) p53 binding or (D to F) p63 binding.
Figure 5—figure supplement 3
Top motifs co-enriched with primary ‘p53+p63’, ‘p53’, and ‘p63’ motifs at the respective DNA sites.
Figure 5—figure supplement 4
TFs with significantly similar binding repertoirs.
Top 20 TFs with ChIP-seq peak sets similar to (A) the common p53+p63 sites, (B) the unique p53 sites, and (C) the unique p63 sites (Figure 5E) as identified using CistromeDB toolkit.
Of note, some TP53 ChIP-seq datasets are wrongly labeled ‘T’ in the database.
Figure 6
The DNA-binding landscape of p53.
DNA sites occupied by p53 in at least five datasets were searched iterative with the motifs identified by our iterative de novo search (Figure 5F). We searched first for the primary ‘p53+p63’ motif …
Figure 7 with 1 supplement
The DNA-binding landscape of p63.
DNA sites occupied by p63 in at least five datasets were searched iterative with the motifs identified by our iterative de novo search (Figure 5F). We searched first for the primary ‘p53+p63’ motif …
Figure 7—figure supplement 1
Complement to Table 1.
Genes identified as significantly up- or down-regulated in at least the half of all datasets (|p63 Expression Score|| ≥ 8) that are linked to p63-binding sites supported by at least half of all …
Figure 8 with 1 supplement
p63/SCC 28-gene set correlates with poorer survival in HNSC.
Kaplan-Meier plots of TCGA HNSC patient survival data. (A) Patients were subdivided in four equally sized subgroups based on expression levels of the 28-gene set. The results suggest a poorer …
Figure 8—figure supplement 1
Extension of Figure 8C and D.
Boxplot in bins of 10 of TP63 FPKM expression values in TCGA HNCS patient sample data compared to (A) FPKM values of a meta-gene comprising the 28-gene set and (B) ssGSEA scores of the 28-gene set. C…
Tables
Table 1
High-probability direct p63 target genes.
Genes identified as significantly up- or down-regulated in at least the half of all datasets (|p63 Expression Score| ≥ 8) that are linked to p63-binding sites supported by at least half of all …
| Gene symbol | p63 Expression Score | p63 binding within 5 kb from TSS | p63 binding linked through enhancer | Gene symbol | p63 Expression Score | p63 binding within 5 kb from TSS | p63 binding linked through enhancer |
|---|---|---|---|---|---|---|---|
| DUSP6 | 14 | yes | yes | FSCN1 | 8 | yes | yes |
| RAB38 | 14 | yes | yes | GINS3 | 8 | yes | no |
| GSDME | 13 | yes | yes | GM2A | 8 | yes | yes |
| LAD1 | 13 | yes | yes | HMGA2 | 8 | yes | yes |
| S100A2 | 13 | yes | yes | HSPA4L | 8 | yes | yes |
| TMEM40 | 13 | yes | yes | JAG1 | 8 | yes | yes |
| FGFBP1 | 12 | yes | yes | KCTD12 | 8 | yes | no |
| HAS3 | 12 | yes | no | KIAA0930 | 8 | yes | yes |
| NECTIN1 | 12 | yes | yes | KIF14 | 8 | no | yes |
| TCOF1 | 12 | yes | yes | KIRREL1 | 8 | no | yes |
| DUSP7 | 11 | yes | yes | LIG1 | 8 | yes | yes |
| IL1B | 11 | no | yes | LPAR3 | 8 | yes | yes |
| MREG | 11 | no | yes | LRRFIP2 | 8 | no | yes |
| PA2G4 | 11 | yes | no | MALT1 | 8 | no | yes |
| RGS20 | 11 | yes | no | MAST4 | 8 | no | yes |
| SDC1 | 11 | no | yes | MCM3 | 8 | no | yes |
| SFN | 11 | yes | yes | MMP14 | 8 | yes | yes |
| STK17A | 11 | yes | yes | MMRN2 | 8 | yes | no |
| VSNL1 | 11 | yes | yes | NOM1 | 8 | yes | no |
| ARHGAP25 | 10 | yes | yes | NRCAM | 8 | yes | yes |
| CDCA4 | 10 | yes | yes | NRG1 | 8 | no | yes |
| DUSP11 | 10 | yes | no | OAS3 | 8 | yes | yes |
| FAT2 | 10 | yes | no | PPFIBP1 | 8 | yes | yes |
| FERMT1 | 10 | yes | yes | PROCR | 8 | yes | no |
| IL4R | 10 | yes | yes | QSOX2 | 8 | yes | yes |
| INPP1 | 10 | yes | yes | RAD51C | 8 | yes | yes |
| IRF6 | 10 | no | yes | RASSF6 | 8 | no | yes |
| ITGA6 | 10 | no | yes | RFX7 | 8 | yes | no |
| KIZ | 10 | yes | no | SH3PXD2A | 8 | no | yes |
| MAPKBP1 | 10 | no | yes | SLC1A5 | 8 | yes | yes |
| MYO10 | 10 | yes | yes | SLC2A9 | 8 | yes | yes |
| MYO19 | 10 | yes | yes | SLC37A2 | 8 | yes | no |
| ORC1 | 10 | no | yes | SMAD5 | 8 | yes | no |
| PAK1 | 10 | yes | no | SPATS2 | 8 | no | yes |
| PTHLH | 10 | yes | yes | SSRP1 | 8 | no | yes |
| SMTN | 10 | yes | no | TGFB1 | 8 | yes | yes |
| WDFY2 | 10 | yes | no | TMEM237 | 8 | yes | no |
| XDH | 10 | yes | yes | TOMM34 | 8 | yes | no |
| ARHGDIB | 9 | yes | yes | TRIM7 | 8 | yes | yes |
| AURKB | 9 | yes | no | TRIP13 | 8 | yes | no |
| BTBD11 | 9 | yes | no | TSPAN5 | 8 | yes | no |
| C6orf106 | 9 | yes | no | TSR1 | 8 | no | yes |
| CARD10 | 9 | yes | yes | TYMS | 8 | yes | yes |
| CHAF1A | 9 | no | yes | UCK2 | 8 | yes | yes |
| CSTA | 9 | yes | no | UTP4 | 8 | no | yes |
| CYP27B1 | 9 | yes | no | YAP1 | 8 | yes | no |
| FEZ1 | 9 | yes | yes | YES1 | 8 | yes | yes |
| GNA15 | 9 | yes | no | ZFP36L2 | 8 | no | yes |
| GPX2 | 9 | yes | no | APH1B | -8 | no | yes |
| GSTP1 | 9 | yes | no | BIRC3 | -8 | yes | yes |
| HRAS | 9 | yes | yes | C9orf3 | -8 | yes | yes |
| IFI16 | 9 | yes | yes | CHST3 | -8 | no | yes |
| KREMEN1 | 9 | yes | yes | CPQ | -8 | no | yes |
| LDLR | 9 | yes | no | DUSP8 | -8 | yes | no |
| MAPK6 | 9 | yes | yes | EPCAM | -8 | no | yes |
| MYO5A | 9 | no | yes | ERBB2 | -8 | no | yes |
| NCAPH2 | 9 | yes | no | FBN1 | -8 | no | yes |
| NDE1 | 9 | yes | yes | ITFG1 | -8 | yes | no |
| NDST1 | 9 | yes | yes | LLGL2 | -8 | yes | yes |
| NIPAL4 | 9 | yes | yes | NCSTN | -8 | no | yes |
| PPIF | 9 | no | yes | OPN3 | -8 | no | yes |
| PPP4R4 | 9 | yes | no | PBX1 | -8 | yes | yes |
| PTTG1 | 9 | yes | yes | PDXK | -8 | no | yes |
| RAPGEF5 | 9 | yes | yes | PLAC8 | -8 | yes | yes |
| RNASE7 | 9 | yes | yes | S100A4 | -8 | no | yes |
| RRP12 | 9 | no | yes | SPOCK1 | -8 | no | yes |
| SERPINB13 | 9 | yes | no | TNS3 | -8 | no | yes |
| SNCA | 9 | no | yes | ARL6IP5 | -9 | no | yes |
| STX6 | 9 | yes | no | COBL | -9 | no | yes |
| AK4 | 8 | no | yes | CUEDC1 | -9 | yes | yes |
| ARHGAP23 | 8 | yes | yes | GSN | -9 | yes | no |
| ASCC3 | 8 | yes | yes | PDGFC | -9 | yes | yes |
| BRCA1 | 8 | yes | no | PGPEP1 | -9 | no | yes |
| BTBD10 | 8 | yes | yes | PLXNB2 | -9 | yes | yes |
| CCNK | 8 | yes | no | PXDN | -9 | no | yes |
| CCT4 | 8 | yes | no | RALGPS1 | -9 | yes | yes |
| CD44 | 8 | yes | yes | ROR1 | -9 | yes | no |
| CDC42SE1 | 8 | yes | no | SLC16A5 | -9 | yes | yes |
| CDCA7 | 8 | yes | no | TM4SF1 | -9 | yes | yes |
| COL17A1 | 8 | yes | no | ALDH3B1 | −10 | yes | yes |
| CRKL | 8 | yes | yes | CYP1B1 | −10 | no | yes |
| DRAP1 | 8 | yes | yes | HHAT | −10 | yes | yes |
| EHD4 | 8 | no | yes | MEGF8 | −10 | no | yes |
| ERCC6L | 8 | no | yes | PTGES | −10 | yes | no |
| ESRP1 | 8 | no | yes | PTTG1IP | −10 | no | yes |
| FABP5 | 8 | yes | no | RPS27L | −10 | yes | yes |
| FANCI | 8 | yes | yes | SECTM1 | −10 | yes | yes |
| FLOT2 | 8 | yes | no | SLC22A5 | −10 | yes | no |
| FOSL1 | 8 | yes | yes | TNFSF15 | −10 | yes | yes |
| FRMD4B | 8 | yes | no | SRD5A3 | −11 | yes | no |
Additional files
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Supplementary file 1
Detailed information on publicly available p63-dependent gene expression profiling and p63 ChIP-seq datasets that were integrated in this study.
- https://cdn.elifesciences.org/articles/63266/elife-63266-supp1-v2.xlsx
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Supplementary file 2
Meta-analysis from 16 p63-dependent gene expression information datasets (listed in Suppelemtary File 1) to generate the p63 Expression Score for 19,156 human genes.
- https://cdn.elifesciences.org/articles/63266/elife-63266-supp2-v2.xlsx
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Supplementary file 3
p63- and p53-binding sites identified in at least 5 out of 20 and 28 ChIP-seq datasets, respectively.
Binding sites are listed with their ChIP-seq dataset support and highest scoring p63 response elements (p63REs) or p53REs. Genes associated with p63-binding sites through proximal TSS binding or enhancers are listed.
- https://cdn.elifesciences.org/articles/63266/elife-63266-supp3-v2.xlsx
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Transparent reporting form
- https://cdn.elifesciences.org/articles/63266/elife-63266-transrepform-v2.docx
