Regulation of pluripotency in male germline stem cells by Dmrt1
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
Abstract
Spermatogonial stem cells (SSCs) present the potential to acquire pluripotency under specific culture conditions. However, the frequency of pluripotent cell derivation is low, and the mechanism of SSC reprogramming remains unknown. In this study, we report that induction of global DNA hypomethylation in germline stem (GS) cells (cultured SSCs) induces pluripotent cell derivation. When DNA demethylation was triggered by Dnmt1 depletion, GS cells underwent apoptosis. However, GS cells were converted into embryonic stem (ES)-like cells by double knockdown of Dnmt1 and p53. This treatment down-regulated Dmrt1, a gene involved in sexual differentiation, meiosis, and pluripotency. Dmrt1 depletion caused apoptosis of GS cells, but a combination of Dmrt1 and p53 depletion also induced pluripotency. Functional screening of putative Dmrt1 target genes revealed that Dmrt1 depletion up-regulates Sox2. Sox2 transfection up-regulated Oct4 and produced pluripotent cells. This conversion was enhanced by Oct1 depletion, suggesting that the balance of Oct proteins maintains SSC identity. These results suggest that spontaneous SSC reprogramming is caused by unstable DNA methylation and that a Dmrt1-Sox2 cascade is critical for regulating pluripotency in SSCs.
Details
Original language | English |
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Pages (from-to) | 1949-58 |
Number of pages | 10 |
Journal | Genes & development |
Volume | 27 |
Issue number | 18 |
Publication status | Published - 15 Sept 2013 |
Peer-reviewed | Yes |
Externally published | Yes |
External IDs
PubMedCentral | PMC3792472 |
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Scopus | 84884547239 |
Keywords
Keywords
- Animals, Cell Line, Cellular Reprogramming/genetics, DNA Methylation, Gene Expression Regulation, Gene Knockdown Techniques, Male, Mice, Mice, Inbred C57BL, Octamer Transcription Factor-1/genetics, Pluripotent Stem Cells/metabolism, SOXB1 Transcription Factors/genetics, Spermatogonia/metabolism, Transcription Factors/genetics, Tumor Suppressor Protein p53/genetics