Stage-Specific Demethylation in Primordial Germ Cells Safeguards against Precocious Differentiation.
Remodeling DNA methylation in mammalian genomes can be global, as seen in preimplantation embryos and primordial germ cells (PGCs), or locus specific, which can regulate neighboring gene expression. In PGCs, global and locus-specific DNA demethylation occur in sequential stages, with an initial global decrease in methylated cytosines (stage I) followed by a Tet methylcytosine dioxygenase (Tet)-dependent decrease in methylated cytosines that act at imprinting control regions (ICRs) and meiotic genes (stage II). The purpose of the two-stage mechanism is unclear. Here we show that Dnmt1 preserves DNA methylation through stage I at ICRs and meiotic gene promoters and is required for the pericentromeric enrichment of 5hmC. We discovered that the functional consequence of abrogating two-stage DNA demethylation in PGCs was precocious germline differentiation leading to hypogonadism and infertility. Therefore, bypassing stage-specific DNA demethylation has significant consequences for progenitor germ cell differentiation and the ability to transmit DNA from parent to offspring.
Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Joseph
J
Hargan-Calvopina
Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Sara
S
Taylor
Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Helene
H
Cook
Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Zhongxun
Z
Hu
Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Serena A
SA
Lee
Institute of Plant and Microbial Biology, Academia Sinica, Taipei 11529, Taiwan.
Ming-Ren
MR
Yen
Institute of Plant and Microbial Biology, Academia Sinica, Taipei 11529, Taiwan.
Yih-Shien
YS
Chiang
Institute of Plant and Microbial Biology, Academia Sinica, Taipei 11529, Taiwan.
Pao-Yang
PY
Chen
Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: clarka@ucla.edu.
Amander T
AT
Clark
D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005854:Germ Cells / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D008540:Meiosis; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism
C508515:DAZL protein, mouse; D016601:RNA-Binding Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse