Implication of DNA Demethylation and Bivalent Hist【DOC精选】.doc

Implication of DNA Demethylation and Bivalent Histone Modification for Selective Gene Regulation in Mouse Primordial Germ Cells Kentaro Mochizuki,1 Makoto Tachibana,2 Mitinori Saitou,3,4 Yuko Tokitake,1 and Yasuhisa Matsui1,* Introduction Germ cells are the only cells capable of giving rise to truly totipotent cells, via differentiation to sperms/eggs and subsequent fertilization. In mouse embryos at around embryonic day (E) 7.25, a small population of primordial germ cells (PGCs) in the extraembryonic mesoderm and derived from the epiblasts is first “fate-determined”. Shortly before PGC fate determination, cell type-specific expression of Blimp1/Prdm1 and Prdm14 initiates in PGC precursors; these proteins are key transcriptional regulators of PGC development. Blimp1/Prdm1 and Prdm14 repress the somatic mesodermal program [1]–[3]. Furthermore, many pluripotency-related genes, including Oct4, Nanog, and Sox2, are expressed specifically in PGCs [2], [4]. Oct4 plays essential roles in PGCs fate determination [5]. Once fate-determined, PGCs start to migrate to genital ridges, the future gonads; there, they rapidly proliferate and increase in number. A portion of PGCs is eliminated by apoptosis during this period [6]. Nanos3 [7], [8] is initially expressed specifically in PGCs at around PGC fate determination, and it supports survival of migrating PGCs along with Oct4 [9] and Nanog [10], [11]. Genome-wide epigenetic changes also occur in migrating PGCs [summarized in 12], and Prdm14 is involved in this process [3]. After arrival at genital ridges, PGCs undergo further epigenetic changes such as DNA demethylation of imprinted genes and the repetitive sequences [13]. Germ cells thereafter stop proliferation at E14.5, and male germ cells are arrested in G1 phase of cell-cycle, resume proliferation at the time of birth as spermatogonial stem cells and part of them start to differentiate towards spermatozoa. At E14.5, female germ cells immediately enter meiosis, are soon arre