Abstract
BackgroundThe transcription factor p63 belongs to the p53/p63/p73 family and plays key functional roles during normal epithelial development and differentiation and in pathological states such as squamous cell carcinomas. The human TP63 gene, located on chromosome 3q28 is driven by two promoters that generate the full-length transactivating (TA) and N-terminal truncated (ΔN) isoforms. Furthermore alternative splicing at the C-terminus gives rise to additional α, β, γ and likely several other minor variants. Teasing out the expression and biological function of each p63 variant has been both the focus of, and a cause for contention in the p63 field.ResultsHere we have taken advantage of a burgeoning RNA-Seq based genomic data-sets to examine the global expression profiles of p63 isoforms across commonly utilized human cell-lines and major tissues and organs. Consistent with earlier studies, we find ΔNp63 transcripts, primarily that of the ΔNp63α isoforms, to be expressed in most cells of epithelial origin such as those of skin and oral tissues, mammary glands and squamous cell carcinomas. In contrast, TAp63 is not expressed in the majority of normal cell-types and tissues; rather it is selectively expressed at moderate to high levels in a subset of Burkitt’s and diffuse large B-cell lymphoma cell lines. We verify this differential expression pattern of p63 isoforms by Western blot analysis, using newly developed ΔN and TA specific antibodies. Furthermore using unsupervised clustering of human cell lines, tissues and organs, we show that ΔNp63 and TAp63 driven transcriptional networks involve very distinct sets of molecular players, which may underlie their different biological functions.ConclusionsIn this study we report comprehensive and global expression profiles of p63 isoforms and their relationship to p53/p73 and other potential transcriptional co-regulators. We curate publicly available data generated in part by consortiums such as ENCODE, FANTOM and Human Protein Atlas to delineate the vastly different transcriptomic landscapes of ΔNp63 and TAp63. Our studies help not only in dispelling prevailing myths and controversies on p63 expression in commonly used human cell lines but also augur new isoform- and cell type-specific activities of p63.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1793-9) contains supplementary material, which is available to authorized users.
Highlights
The transcriptional networks that govern temporally and spatially regulated gene expression programs are remarkably dynamic and complex [1]
One major factor that bestows this complexity is the incredible diversity of Transcription Factor (TF) isoforms that frequently arise from molecular events such as alternative splicing and promoter usage [2]
We mined publicly available RNA-Seq databases generated by the ENCODE project and existing literature to obtain transcriptomic maps of 34 commonly used and well characterized human cell types (Additional file 1: Table S1)
Summary
The transcriptional networks that govern temporally and spatially regulated gene expression programs are remarkably dynamic and complex [1]. One major factor that bestows this complexity is the incredible diversity of Transcription Factor (TF) isoforms that frequently arise from molecular events such as alternative splicing and promoter usage [2]. These isoforms, representing different protein products from the same gene, have distinct biological properties and can shape the transcriptional landscape of any cell in unique fashion. Lack of large-scale expression data sets and appropriate tools such as isoform-specific antibodies have often hampered such studies and led to confusion and contradictory findings This is quite evident in the case of the p53/p63/p73 family of proteins and is true for p63 [3,4,5,6]. Teasing out the expression and biological function of each p63 variant has been both the focus of, and a cause for contention in the p63 field
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