Dissecting the DNA binding landscape and gene regulatory network of p63 and p53.

Konstantin Riege,Arne Sahm,Steve Hoffmann,Simon S Mcdade,Martin Fischer,Helene Kretzmer

doi:10.7554/elife.63266

Abstract

The transcription factor p53 is the best-known tumor suppressor, but its sibling p63 is a master regulator of epidermis development and a key oncogenic driver in squamous cell carcinomas (SCC). Despite multiple gene expression studies becoming available, the limited overlap of reported p63-dependent genes has made it difficult to decipher the p63 gene regulatory network. Particularly, analyses of p63 response elements differed substantially among the studies. To address this intricate data situation, we provide an integrated resource that enables assessing the p63-dependent regulation of any human gene of interest. We use a novel iterative de novo motif search approach in conjunction with extensive ChIP-seq data to achieve a precise global distinction between p53-and p63-binding sites, recognition motifs, and potential co-factors. We integrate these data with enhancer:gene associations to predict p63 target genes and identify those that are commonly de-regulated in SCC representing candidates for prognosis and therapeutic interventions.

Highlights

In contrast to the tumor suppressor p53 with its extensive set of target genes controlling the cell cycle and apoptosis (Fischer, 2017; Sammons et al, 2020), its phylogenetically ancient sibling p63 (DNp63) governs epidermis development (Mills et al, 1999; Yang et al, 1999) and is an oncogenic driver of squamous cell carcinoma (SCC) (Cancer Genome Atlas Research Network et al, 2018; Gatti et al, 2019) that is overexpressed or amplified in SCCs, which depend on its expression (Ramsey et al, 2013)
P63 (DNp63) is known as master regulator in epidermis development and more recently emerged as a key oncogenic factor in SCC, a comprehensive assessment of the gene regulatory network (GRN) commonly controlled by p63 and its comparison to the GRN commonly controlled by the closely related tumor suppressor p53 has been missing
An increasing number of available high-throughput datasets enabled us to generate ranked lists of p63-regulated genes and p63-bound DNA sites that together reveal high-probability direct p63 target genes regulated by p63 across cells of multiple origins

Summary

Introduction

In contrast to the tumor suppressor p53 with its extensive set of target genes controlling the cell cycle and apoptosis (Fischer, 2017; Sammons et al, 2020), its phylogenetically ancient sibling p63 (DNp63) governs epidermis development (Mills et al, 1999; Yang et al, 1999) and is an oncogenic driver of squamous cell carcinoma (SCC) (Cancer Genome Atlas Research Network et al, 2018; Gatti et al, 2019) that is overexpressed or amplified in SCCs, which depend on its expression (Ramsey et al, 2013). The TP53 and TP63 genes encode for two major isoform groups that are controlled by distinct promoters leading to transcripts differing in their N-terminus (Murray-Zmijewski et al, 2006). The long isoform TAp63 is predominantly expressed in germ cells, while the smaller transcript, DNp63, is most copious in stratifying epithelia (Sethi et al, 2015). Similar to p53, alternative splicing leads to a, b, and g protein isoforms that differ in their C-terminus (Murray-Zmijewski et al, 2006). While both TAp63 and DNp63 may bind to DNA through a specific binding domain, DNp63 lacks the canonical N-terminal transactivation

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Conclusion