Abstract
The roles of microRNAs (miRNAs) and the miRNA processing machinery in the regulation of stem cell biology are not well understood. Here, we show that the p53 family member and p63 isoform, ΔNp63, is a transcriptional activator of a cofactor critical for miRNA processing (DGCR8). This regulation gives rise to a unique miRNA signature resulting in reprogramming cells to multipotency. Strikingly, ΔNp63(-/-) epidermal cells display profound defects in terminal differentiation and express a subset of markers and miRNAs present in embryonic stem cells and fibroblasts induced to pluripotency using Yamanaka factors. Moreover, ΔNp63(-/-) epidermal cells transduced with an inducible DGCR8 plasmid can differentiate into multiple cell fates in vitro and in vivo. We found that human primary keratinocytes depleted of ΔNp63 or DGCR8 can be reprogrammed in 6 d and express a unique miRNA and gene expression signature that is similar but not identical to human induced pluripotent stem cells. Our data reveal a role for ΔNp63 in the transcriptional regulation of DGCR8 to reprogram adult somatic cells into multipotent stem cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Animals
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Cell Differentiation
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Cell Line
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Cell Lineage
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Cell Proliferation
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Chimera
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Down-Regulation / genetics*
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Embryo, Mammalian / cytology
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Epidermal Cells
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Gene Expression Profiling
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Homeodomain Proteins / metabolism
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Humans
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Induced Pluripotent Stem Cells / cytology
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Induced Pluripotent Stem Cells / metabolism
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Keratinocytes / cytology
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Keratinocytes / metabolism*
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Mice
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MicroRNAs / genetics
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MicroRNAs / metabolism
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Multipotent Stem Cells / cytology*
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Multipotent Stem Cells / metabolism
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Nanog Homeobox Protein
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Octamer Transcription Factor-3 / metabolism
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Phosphoproteins / deficiency
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Phosphoproteins / genetics*
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Phosphoproteins / metabolism
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Proteins / genetics*
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Proteins / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA-Binding Proteins / genetics*
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RNA-Binding Proteins / metabolism
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SOXB1 Transcription Factors / metabolism
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Trans-Activators / deficiency
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Trans-Activators / genetics*
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Trans-Activators / metabolism
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Transcription Factors / deficiency
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Transcription, Genetic
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / genetics*
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Tumor Suppressor Proteins / metabolism
Substances
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DGCR8 protein, human
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Dgcr8 protein, mouse
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Homeodomain Proteins
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MicroRNAs
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Nanog Homeobox Protein
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Nanog protein, mouse
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Octamer Transcription Factor-3
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Phosphoproteins
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Pou5f1 protein, mouse
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Proteins
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RNA, Messenger
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RNA-Binding Proteins
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SOXB1 Transcription Factors
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Sox2 protein, mouse
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TP63 protein, human
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Trans-Activators
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Transcription Factors
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Trp63 protein, mouse
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Tumor Suppressor Proteins