Mutant p63 Affects Epidermal Cell Identity through Rewiring the Enhancer Landscape

Abstract

Highlights d Downregulated epidermal genes and upregulated nonepidermal genes in EEC keratinocytes d A genome-wide redistribution of enhancers in EEC keratinocytes d Gained enhancers are frequently bound by deregulated RUNX1 in EEC keratinocytes d siRUNX1 partially rescues gene deregulation and the altered enhancer landscape

RUNX transcription factors: orchestrators of development

“…Additionally, RUNX1 has been implicated in the lipid metabolism of skin epithelial cells by regulating fatty acid production (Jain et al, 2018). Runx1 is also expressed in mouse keratinocytes, where it collaborates with p63 (Trp63) to regulate the balance between proliferation and differentiation (Masse et al, 2012;Qu et al, 2018). In addition to Runx1, Runx2 is expressed in the dermal papillae and the bulb epithelium (Glotzer et al, 2008), whereas Runx3 is expressed in the dermal layer in placode and hair germ stages, and in the dermal papillae throughout the hair cycle (Raveh et al, 2005).…”

TP63 links chromatin remodeling and enhancer reprogramming to epidermal differentiation and squamous cell carcinoma development

“…Interestingly, either ΔNp63α or KLF4 alone could not induce expression of keratin 14 [ 66 ], suggesting the interaction between ΔNp63α and KLF4 is required for full epidermal commitment. EEC syndrome patients display keratinocytes harboring p63 mutations, which lack DNA-binding ability, and display a loss of enhancers at epidermal-expressing genes, indicating that ΔNp63α binding of DNA is necessary to establish the epidermal enhancer landscape and epidermal commitment [ 64 , 77 ]. Furthermore, the majority of p63-bound epidermal enhancers lose their accessibility in p63 knockout ESC during in vitro differentiation [ 59 ].…”

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

“…Given that p63 regulates many target genes through enhancers (Kouwenhoven et al, 2015a;Lin-Shiao et al, 2018, 2019Qu et al, 2018;Somerville et al, 2018), straight forward integration of differential gene regulation data and p63 binding data based on proximity binding to a gene's TSS is unlikely to capture all direct p63 target genes. To resolve this issue, we integrated the p63 binding data and the p63 Expression Score based on enhancer:gene association information (Fishilevich et al, 2017) in addition to proximity binding to TSSs to predict direct p63 target genes.…”

“…However, ΔNp63 has also been shown to harbor alternative TADs, that endow transactivation activity (Helton et al, 2006;King et al, 2003;Yang et al, 2006). Notably, the many ΔNp63 binding sites are associated with enhancer regions, where ΔNp63 has been proposed to "bookmark" genes that are expressed in stratifying epithelia (Karsli Uzunbas et al, 2019;Kouwenhoven et al, 2015a;Lin-Shiao et al, 2019;Qu et al, 2018;Somerville et al, 2018). Here, we focus on the most widely expressed isoforms p53α (hereafter p53) and ΔNp63 (hereafter p63).…”

“…This is in part due to the limited overlap of the p63-dependent genes identified in individual studies (Kouwenhoven et al, 2015b). Also, the frequent binding of p63 to enhancers (Kouwenhoven et al, 2015a;Lin-Shiao et al, 2018, 2019Qu et al, 2018;Somerville et al, 2018) and the difficulty to associate such enhancers with target gene regulation adds another level of complexity to the quest of describing the GRN. To overcome these limitations, we utilize a recently developed metaanalysis approach (Fischer et al, 2016a), which helped us to dissect the GRNs of the mouse and human orthologue of p53 (Fischer, 2019).…”