Regulation of pluripotency in male germline stem cells by Dmrt1

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Seiji Takashima - , Kyoto University (Author)
  • Michiko Hirose - (Author)
  • Narumi Ogonuki - (Author)
  • Miki Ebisuya - , Kyoto University (Author)
  • Kimiko Inoue - (Author)
  • Mito Kanatsu-Shinohara - (Author)
  • Takashi Tanaka - (Author)
  • Eisuke Nishida - (Author)
  • Atsuo Ogura - (Author)
  • Takashi Shinohara - (Author)

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 languageEnglish
Pages (from-to)1949-58
Number of pages10
JournalGenes & development
Volume27
Issue number18
Publication statusPublished - 15 Sept 2013
Peer-reviewedYes
Externally publishedYes

External IDs

PubMedCentral PMC3792472
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