Transcription factor p63 bookmarks and regulates dynamic enhancers during epidermal differentiation

Abstract

The transcription factor p63 plays a pivotal role in keratinocyte proliferation and differentiation in the epidermis. However, how p63 regulates epidermal genes during differentiation is not yet clear. Using epigenome profiling of differentiating human primary epidermal keratinocytes, we characterized a catalog of dynamically regulated genes and p63-bound regulatory elements that are relevant for epithelial development and related diseases. p63-bound regulatory elements occur as single or clustered enhancers, and remarkably, only a subset is active as defined by the co-presence of the active enhancer mark histone modification H3K27ac in epidermal keratinocytes. We show that the dynamics of gene expression correlates with the activity of p63-bound enhancers rather than with p63 binding itself. The activity of p63-bound enhancers is likely determined by other transcription factors that cooperate with p63. Our data show that inactive p63-bound enhancers in epidermal keratinocytes may be active during the development of other epithelial-related structures such as limbs and suggest that p63 bookmarks genomic loci during the commitment of the epithelial lineage and regulates genes through temporal- and spatial-specific active enhancers.

p63 supports aerobic respiration through hexokinase II

“…In our experimental set, neither p53 nor p63 transactivated the human promoter (Fig. 3D), but a further investigation of the genomic sequence, taking advantage of the genomewide p63 ChIP-Seq profiles in human keratinocytes from a previous study (21,22), noted a specific p63 binding element in the 15th intronic region of the genomic sequence ( Fig. 3C and Fig.…”

Learning from regeneration research organisms: The circuitous road to scar free wound healing

“…p63 plays a pivotal role in epidermal development but also has a key role in regulating keratinocyte homeostasis in mature skin (Borrelli et al, 2010; Kouwenhoven et al, 2015; McDade and McCance, 2010; Pozzi et al, 2009; Testoni et al, 2006; Truong et al, 2006). Depletion of p63 in keratinocytes results in decreased proliferation and a subsequent loss of stratified epithelium (Truong et al, 2006).…”

Predicting double-strand DNA breaks using epigenome marks or DNA at kilobase resolution

“…ChIP-seq and DNase-seq peaks in NHEKs, as obtained from the ENCODE project, were mapped to corresponding DSB and non-DSB sites [7]. We also mapped p63 ChIP-seq peaks from keratinocytes [21]. We further searched for potential protein-binding sites at DSB and non-DSB sites using motif position weight matrices from the JASPAR 2016 database [22], and predicted DNA shape at DSB and non-DSB sites using Monte Carlo simulations [23].…”

“…We used ChIP-seq uniform peaks (CTCF, POL2B, EZH2, H3K4me1/me2/me3, H3K9me1/me3/ac, H3K27me3/ac, H3K36me3, H3K79me2, H4K20me1, and H2A.Z) and DNase-seq uniform peaks for NHEKs from the ENCODE project [7] (https://genome.ucsc.edu/ encode). We also used p63 ChIP-seq of keratinocytes from GEO accession GSE59827 [21].…”