Induced multipotency in adult keratinocytes through down-regulation of ΔNp63 or DGCR8.
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.
Departments of Biochemistry and Molecular Biology, Immunology, and Dermatology and Graduate School of Biomedical Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
Deepavali
D
Chakravarti
Xiaohua
X
Su
Min Soon
MS
Cho
Ngoc Hoang Bao
NH
Bui
Cristian
C
Coarfa
Avinashnarayan
A
Venkatanarayan
Ashley L
AL
Benham
Ramón E
RE
Flores González
Jennifer
J
Alana
Weimin
W
Xiao
Marco L
ML
Leung
Harina
H
Vin
Io Long
IL
Chan
Arianexys
A
Aquino
Nicole
N
Müller
Hongran
H
Wang
Austin J
AJ
Cooney
Jan
J
Parker-Thornburg
Kenneth Y
KY
Tsai
Preethi H
PH
Gunaratne
Elsa R
ER
Flores
D000328:Adult; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D049109:Cell Proliferation; D002678:Chimera; D015536:Down-Regulation / Q000235:genetics*; D004622:Embryo, Mammalian / Q000166:cytology; D000078404:Epidermal Cells; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
C474043:DGCR8 protein, human; C474044:Dgcr8 protein, mouse; D018398:Homeodomain Proteins; D035683:MicroRNAs; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; D010750:Phosphoproteins; C494174:Pou5f1 protein, mouse; D011506:Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D025521:Tumor Suppressor Proteins