title: Genome-wide analysis of the p53 gene regulatory network in the developing mouse kidney.
abstract: Despite mounting evidence that p53 senses and responds to physiological cues in vivo, existing knowledge regarding p53 function and target genes is largely derived from studies in cancer or stressed cells. Herein we utilize p53 transcriptome and ChIP-Seq (chromatin immunoprecipitation-high throughput sequencing) analyses to identify p53 regulated pathways in the embryonic kidney, an organ that develops via mesenchymal-epithelial interactions. This integrated approach allowed identification of novel genes that are possible direct p53 targets during kidney development. We find the p53-regulated transcriptome in the embryonic kidney is largely composed of genes regulating developmental, morphogenesis, and metabolic pathways. Surprisingly, genes in cell cycle and apoptosis pathways account for <5% of differentially expressed transcripts. Of 7,893 p53-occupied genomic regions (peaks), the vast majority contain consensus p53 binding sites. Interestingly, 78% of p53 peaks in the developing kidney lie within proximal promoters of annotated genes compared with 7% in a representative cancer cell line; 25% of the differentially expressed p53-bound genes are present in nephron progenitors and nascent nephrons, including key transcriptional regulators, components of Fgf, Wnt, Bmp, and Notch pathways, and ciliogenesis genes. The results indicate widespread p53 binding to the genome in vivo and context-dependent differences in the p53 regulon between cancer, stress, and development. To our knowledge, this is the first comprehensive analysis of the p53 transcriptome and cistrome in a developing mammalian organ, substantiating the role of p53 as a bona fide developmental regulator. We conclude p53 targets transcriptional networks regulating nephrogenesis and cellular metabolism during kidney development.
authors.affiliation: Section of Pediatric Nephrology, Department of Pediatrics, Tulane University Health Sciences Center, New Orleans, Louisiana;
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Li
authors.forename: Jiao
authors.initials: J
authors.lastname: Liu
authors.forename: Nathan
authors.initials: N
authors.lastname: McLaughlin
authors.forename: Dimcho
authors.initials: D
authors.lastname: Bachvarov
authors.forename: Zubaida
authors.initials: Z
authors.lastname: Saifudeen
authors.forename: Samir S
authors.initials: SS
authors.lastname: El-Dahr
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D005809:Genes, Regulator; D017930:Genes, Reporter; D016678:Genome / Q000235:genetics*; D007668:Kidney / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000235:genetics; D009399:Nephrons / Q000378:metabolism; D059372:Nucleotide Motifs / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding / Q000235:genetics; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D002843:Chromatin; D016159:Tumor Suppressor Protein p53
keywords: ChIP-Seq; differentiation; gene expression; kidney development; nephrogenesis; p53; signaling pathways