DNMT3L promotes quiescence in postnatal spermatogonial progenitor cells.
The ability of adult stem cells to reside in a quiescent state is crucial for preventing premature exhaustion of the stem cell pool. However, the intrinsic epigenetic factors that regulate spermatogonial stem cell quiescence are largely unknown. Here, we investigate in mice how DNA methyltransferase 3-like (DNMT3L), an epigenetic regulator important for interpreting chromatin context and facilitating de novo DNA methylation, sustains the long-term male germ cell pool. We demonstrated that stem cell-enriched THY1(+) spermatogonial stem/progenitor cells (SPCs) constituted a DNMT3L-expressing population in postnatal testes. DNMT3L influenced the stability of promyelocytic leukemia zinc finger (PLZF), potentially by downregulating Cdk2/CDK2 expression, which sequestered CDK2-mediated PLZF degradation. Reduced PLZF in Dnmt3l KO THY1(+) cells released its antagonist, Sal-like protein 4A (SALL4A), which is associated with overactivated ERK and AKT signaling cascades. Furthermore, DNMT3L was required to suppress the cell proliferation-promoting factor SALL4B in THY1(+) SPCs and to prevent premature stem cell exhaustion. Our results indicate that DNMT3L is required to delicately balance the cycling and quiescence of SPCs. These findings reveal a novel role for DNMT3L in modulating postnatal SPC cell fate decisions.
Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
Hung-Fu
HF
Liao
Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan.
Wendy S C
WS
Chen
Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan.
Yu-Hsiang
YH
Chen
Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan.
Tzu-Hao
TH
Kao
Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan.
Yen-Tzu
YT
Tseng
Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 106, Taiwan.
Chien-Yueh
CY
Lee
Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 106, Taiwan.
Yu-Chiao
YC
Chiu
Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan.
Pei-Lung
PL
Lee
Department of Biochemistry, Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan.
Qian-Jia
QJ
Lin
Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan.
Yung-Hao
YH
Ching
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Okura, Setagaya, Tokyo 157-8535, Japan.
Kenichiro
K
Hata
Department of Animal Science and Biotechnology, Tunghai University, Taichung 40704, Taiwan.
Winston T K
WT
Cheng
Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan.
Mong-Hsun
MH
Tsai
Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
Hiroyuki
H
Sasaki
Department of Obstetrics and Gynecology, College of Medicine and the Hospital, National Taiwan University, Taipei 100, Taiwan.
Hong-Nerng
HN
Ho
Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan.
Shinn-Chih
SC
Wu
Department of Biochemistry, Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan.
Yen-Hua
YH
Huang
Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
Pauline
P
Yen
Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan Center for Systems Biology, National Taiwan University, Taipei 106, Taiwan Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei 106, Taiwan shaupinglin@ntu.edu.tw.
Shau-Ping
SP
Lin
D053687:Adult Stem Cells / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D049109:Cell Proliferation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000502:physiology*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D044127:Epigenesis, Genetic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006579:Heterozygote; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013093:Spermatogonia / Q000378:metabolism*; D013737:Testis / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; C509167:Sall4 protein, mouse; D014157:Transcription Factors; C498796:Dnmt3l protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
DNMT3L; Mouse; Proliferation; Quiescence; Spermatogonial progenitor cell