Mapping the p53 transcriptome universe using p53 natural polymorphs.
The tumor suppressor p53 has defined roles in varied cellular processes including apoptosis and DNA repair. While conventional genomic approaches have suggested a large number of p53 targets, there is a need for a systematic approach to validate these putative genes. We developed a method to identify and validate p53's transcriptional behavior by utilizing 16 non-synonymous p53 single-nucleotide polymorphism (SNP) variants. Five SNPs located within the DNA-binding domain of p53 were found to be functionally null, whereas the other 11 SNPs were p53WT-like in behavior. By integrating p53 ChIP-seq analysis with transcriptome data from the p53 SNP variants, 592 genes were identified as novel p53 targets. Many of these genes mapped to previously less well-characterized aspects of p53 function, such as cell signalling, metabolism, central nervous system, and immune system. These data provide pivotal insights into the involvement of p53 in diverse pathways of normal physiological processes and open new avenues for investigation of p53 function.
Singapore Immunology Network, A*STAR, 8A Biomedical Grove, 138648 Singapore.
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Wang
Singapore Immunology Network, A*STAR, 8A Biomedical Grove, 138648 Singapore.
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Niu
1] Singapore Immunology Network, A*STAR, 8A Biomedical Grove, 138648 Singapore [2] Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore.
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Lam
Singapore Immunology Network, A*STAR, 8A Biomedical Grove, 138648 Singapore.
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Xiao
1] Singapore Immunology Network, A*STAR, 8A Biomedical Grove, 138648 Singapore [2] Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore.
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Ren
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D053263:Gene Regulatory Networks; D045325:HCT116 Cells; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D059467:Transcriptome / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050797:STAT4 Transcription Factor; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D004247:DNA