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.
Subject(s)
Down-Regulation/genetics , Keratinocytes/metabolism , Multipotent Stem Cells/cytology , Phosphoproteins/genetics , Proteins/genetics , RNA-Binding Proteins/genetics , Trans-Activators/genetics , Transcription Factors/genetics , Tumor Suppressor Proteins/genetics , Adult , Animals , Cell Differentiation , Cell Line , Cell Lineage , Cell Proliferation , Chimera , Embryo, Mammalian/cytology , Epidermal Cells , Gene Expression Profiling , Homeodomain Proteins/metabolism , Humans , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/metabolism , Keratinocytes/cytology , Mice , MicroRNAs/genetics , MicroRNAs/metabolism , Multipotent Stem Cells/metabolism , Nanog Homeobox Protein , Octamer Transcription Factor-3/metabolism , Phosphoproteins/deficiency , Phosphoproteins/metabolism , Proteins/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA-Binding Proteins/metabolism , SOXB1 Transcription Factors/metabolism , Trans-Activators/deficiency , Trans-Activators/metabolism , Transcription Factors/deficiency , Transcription Factors/metabolism , Transcription, Genetic , Tumor Suppressor Proteins/deficiency , Tumor Suppressor Proteins/metabolismABSTRACT
A diverse 20-compound library of analogues based on the marine alkaloid oroidin were synthesized via a reductive acylation strategy. The final target was then assayed for inhibition and dispersion activity against common proteobacteria known to form biofilms. This methodology represents a significant improvement over the generality of known methods to acylate substrates containing 2-aminoimidazoles and has the potential to have broad application to the synthesis of more advanced oroidin family members and their corresponding analogues.
