Abstract
BackgroundThe Transcription Factor (TF) p63 is a master regulator of epidermal development and differentiation as evident from the remarkable skin phenotype of p63 mouse knockouts. Furthermore, ectopic expression of p63 alone is sufficient to convert simple epithelium into stratified epithelial tissues in vivo and p63 is required for efficient transdifferentiation of fibroblasts into keratinocytes. However, little is known about the molecular mechanisms of p63 function, in particular how it selects its target sites in the genome. p63, which acts both as an activator and repressor of transcription, recognizes a canonical binding motif that occurs over 1 million times in the human genome. But, in human keratinocytes less than 12,000 of these sites are bound in vivo suggesting that underlying chromatin architecture and cooperating TFs mediate p63-genome interactions.ResultsWe find that the chromatin architecture at p63-bound targets possess distinctive features and can be used to categorize p63 targets into proximal promoters (1%), enhancers (59%) and repressed or inactive (40%) regulatory elements. Our analysis shows that the chromatin modifications H3K4me1, H3K27me3, along with overall chromatin accessibility status can accurately predict bonafide p63-bound sites without a priori DNA sequence information. Interestingly, however there exists a qualitative correlation between the p63 binding motif and accessibility and H3K4me1 levels. Furthermore, we use a comprehensive in silico approach that leverages ENCODE data to identify several known TFs such as AP1, AP2 and novel TFs (RFX5 for e.g.) that can potentially cooperate with p63 to modulate its myriad biological functions in keratinocytes.ConclusionsOur analysis shows that p63 bound genomic locations in keratinocytes are accessible, marked by active histone modifications, and co-targeted by other developmentally important transcriptional regulators. Collectively, our results suggest that p63 might actively remodel and/or influence chromatin dynamics at its target sites and in the process dictate its own DNA binding and possibly that of adjacent TFs.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-1042) contains supplementary material, which is available to authorized users.
Highlights
The Transcription Factor (TF) p63 is a master regulator of epidermal development and differentiation as evident from the remarkable skin phenotype of p63 mouse knockouts
All p63 isoforms share the DNA-binding and oligomerization domains, which are analogous to that of p53. It is well-established that ΔNp63, especially ΔNp63α is the predominant isoform that is present in most epithelial cells such as the keratinocytes of the skin [9]. Both gene complementation studies and isoform specific knockouts have conclusively affirmed that ΔNp63 harbors most of the function and biological activity of p63, as it pertains to the epithelial tissues [10,11,12,13,14]
In strong agreement with Kouwenhoven et al, by using high stringency conditions (p-value: 1e−10), we identified a reliable and robust dataset of 11632 p63 binding sites that were common among the three biological replicates
Summary
The Transcription Factor (TF) p63 is a master regulator of epidermal development and differentiation as evident from the remarkable skin phenotype of p63 mouse knockouts. Tp63 is an important transcription factor of the p53/ p63/p73 family that dictates a wide range of cellular properties including but not limited to stem cell renewal, lineage choices and maintaining the balance between proliferation and differentiation [1,2] This diverse function of p63 is critical for morphogenesis during development, for epithelial-enriched tissues such as the skin and its appendages such as the hair follicles and mammary glands. All p63 isoforms share the DNA-binding and oligomerization domains, which are analogous to that of p53 It is well-established that ΔNp63, especially ΔNp63α is the predominant isoform that is present in most epithelial cells such as the keratinocytes of the skin [9]. Both gene complementation studies and isoform specific knockouts have conclusively affirmed that ΔNp63 harbors most of the function and biological activity of p63, as it pertains to the epithelial tissues [10,11,12,13,14]
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