Details

Autor(en) / Beteiligte

• Si, Han
• Lu, Hai
• Yang, Xinping
• Jang, Minyoung
• Burnett, Jeffery
• Davis, Sean
• Sun, Hong-wei
• Xiao, Wenming
• Wei, Lai
• Meltzer, Paul
• Waes, Carter Van
• Chen, Zhong

Titel

Abstract 4193: TNF-α dynamically modulates genome-wide cross-regulation of cRel, ΔNp63 and TAp73 promoter binding and gene expression in head and neck cancer: TP53 and NFκB ChIP-Seq in HNSCC

Ist Teil von

• Cancer research (Chicago, Ill.), 2012-04, Vol.72 (8_Supplement), p.4193-4193

Erscheinungsjahr

2012

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Abstract We previously showed that cRel, ΔNp63, and TAp73, members of NF-kappaB and TP53 transcription factor (TF) families, together regulate broad biological processes critical for inflammation and cancer survival. However, the underlying molecular mechanisms explaining the global cross-regulation of transcriptome and interactive signal network have not been revealed. Here, we demonstrate that inflammatory cytokine TNF-α induces a dynamic, genome-wide increase in cRel and ΔNp63 chromatin occupancy after replacing TAp73 binding activity, using Illumina Next Generation ChIP-sequencing and fitting the data into a dynamic Poisson distribution model integrated in MACS. Globally, significant binding peaks (p<10-5) were highly enriched in promoter regions (∼10%). These binding peaks further showed significant enrichment around transcription starting sites (±2000bp), and co-localized peaks for any of the two TFs were prevalent within a distance of ∼200 bp. De novo motif search using Gibbs Sampler indicated that cRel and ΔNp63 bound to p53 motifs while TAp73 binding switched from p53 to AP1 motifs when treated with TNF-α. Motifs from these TFs also co-localized within ∼200 bp. Binding activities of individual transcription factors were validated by ChIP-PCR and oliogo-ELISA based binding assays. In addition, TNF-α modulated 1050 differentially expressed genes detected by microarray, of which one-third exhibited binding activity for at least one TF, and 73 genes were identified with co-binding activities for the three TFs simultaneously. Ingenuity Systems Pathway Analysis (IPA) and Gene Ontology revealed that these genes are enriched in cancer-related transcription factors and signaling pathways. Our data suggest a novel mechanism of genome-wide replacement of TAp73 by cRel and ΔNp63, supporting cross-regulation and interactive network between NF-kappaB and TP53 families. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4193. doi:1538-7445.AM2012-4193