Evolutionary re-wiring of p63 and the epigenomic regulatory landscape in keratinocytes and its potential implications on species-specific gene expression and phenotypes

Abstract

Although epidermal keratinocyte development and differentiation proceeds in similar fashion between humans and mice, evolutionary pressures have also wrought significant species-specific physiological differences. These differences between species could arise in part, by the rewiring of regulatory network due to changes in the global targets of lineage-specific transcriptional master regulators such as p63. Here we have performed a systematic and comparative analysis of the p63 target gene network within the integrated framework of the transcriptomic and epigenomic landscape of mouse and human keratinocytes. We determined that there exists a core set of ∼1600 genomic regions distributed among enhancers and super-enhancers, which are conserved and occupied by p63 in keratinocytes from both species. Notably, these DNA segments are typified by consensus p63 binding motifs under purifying selection and are associated with genes involved in key keratinocyte and skin-centric biological processes. However, the majority of the p63-bound mouse target regions consist of either murine-specific DNA elements that are not alignable to the human genome or exhibit no p63 binding in the orthologous syntenic regions, typifying an occupancy lost subset. Our results suggest that these evolutionarily divergent regions have undergone significant turnover of p63 binding sites and are associated with an underlying inactive and inaccessible chromatin state, indicative of their selective functional activity in the transcriptional regulatory network in mouse but not human. Furthermore, we demonstrate that this selective targeting of genes by p63 correlates with subtle, but measurable transcriptional differences in mouse and human keratinocytes that converges on major metabolic processes, which often exhibit species-specific trends. Collectively our study offers possible molecular explanation for the observable phenotypic differences between the mouse and human skin and broadly informs on the prevailing principles that govern the tug-of-war between evolutionary forces of rigidity and plasticity over transcriptional regulatory programs.

PTPN14 Degradation by High-Risk Human Papillomavirus E7 Limits Keratinocyte Differentiation and Contributes to HPV-Mediated Oncogenesis

“…By using an HPV16 E7 variant that cannot degrade PTPN14 (Figures 1 and 2) and by directly testing the effect of PTPN14 knockout in primary HFK (Figure 4), we determined that PTPN14 loss results in a downregulation of several markers of epidermal cell differentiation. Consistent with this idea, PTPN14 appears to be a target of regulation by p53 in mouse cells, but is likely a p63 target in human cells (79, 86–88). p63 is a master regulator of epidermal development (89).…”

PTPN14 degradation by high-risk human papillomavirus E7 limits keratinocyte differentiation and contributes to HPV-mediated oncogenesis

“…5), we determined that PTPN14 loss results in a downregulation of several markers of epidermal cell differentiation. Consistent with this idea, PTPN14 appears to be a target of regulation by p53 in mouse cells but is likely a p63 target in human cells (79,(86)(87)(88). p63 is a master regulator of epidermal development (89).…”

ΔNp63-driven recruitment of myeloid-derived suppressor cells promotes metastasis in triple-negative breast cancer

“…HCC1806 cells were grown to 80% confluence, and cells were then cross-linked with 1% formaldehyde and processed. ChIP-Seq experiments were performed with 2 independent p63 antibodies using the iDeal ChIP-Seq kit for Transcription Factors (Diagenode) (64).…”