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Turner syndrome (TS) is an X monosomy-related disorder caused by X chromosome nondisjunction during embryonic development. Patients with TS have only one intact X chromosome, with the other either completely or partially lost. TS affects various tissues, including the liver, kidneys, brain, cardiovascular system, and ovaries. These abnormalities are suggested to involve an altered dosage of escape genes that evade X chromosome inactivation. However, the mechanisms and roles of these escape genes in the TS phenotype remain unclear. We hypothesized that the expression levels of escape genes differ between wild-type (WT) and TS cell lines. In this study, we generated induced pluripotent stem cell (iPSC) lines from WT and TS fibroblasts and examined the expression levels of escape genes in both undifferentiated fibroblasts and reprogrammed iPSCs from WT and TS samples. The reprogrammed WT and TS iPSCs exhibited general characteristics of pluripotency, including the expression of pluripotency markers and the potential to differentiate into all three germ layers. Forty-five escape genes were differentially expressed between the WT and TS cell lines. Among these, five genes (ATP7A, PHKA1, EBP, ZFX, and SMC1A) were suggested to be implicated in the TS phenotype. However, further studies using additional cell lines are necessary to clarify the correlation between TS and escape genes. [ABSTRACT FROM AUTHOR]

Mouse primordial germ cells (PGCs) first appear at embryonic day (E)7.25 on the base of the allantois, and then migrate through the hindgut to the genital ridge (3). During migration [...], Meiosis is a germ-cell-specific cell division process through which haploid gametes are produced for sexual reproduction (1). Before the initiation of meiosis, mouse primordial germ cells undergo a series of epigenetic reprogramming steps (2,3), including the global erasure of DNA methylation at the 5-position of cytosine (5mC) in CpG-rich DNA (4,5). Although several epigenetic regulators, such as Dnmt3l and the histone methyltransferases G9a and Prdm9, have been reported to be crucial for meiosis (6), little is known about how the expression of meiotic genes is regulated and how their expression contributes to normal meiosis. Using a loss-of-function approach in mice, here we show that the 5mC-specific dioxygenase Tet1 has an important role in regulating meiosis in mouse oocytes. Tet1 deficiency significantly reduces female germ-cell numbers and fertility. Univalent chromosomes and unresolved DNA double-strand breaks are also observed in Tet1-deficient oocytes. Tet1 deficiency does not greatly affect the genome-wide demethylation that takes place in primordial germ cells, but leads to defective DNA demethylation and decreased expression of a subset of meiotic genes. Our study thus establishes a function for Tet1 in meiosis and meiotic gene activation in female germ cells.

Author(s): Shinsuke Ito [sup.1] [sup.2] , Ana C. D'Alessio [sup.1] [sup.2] , Olena V. Taranova [sup.1] [sup.2] , Kwonho Hong [sup.1] [sup.2] , Lawrence C. Sowers [sup.3] , Yi Zhang [...], Tet proteins and DNA demethylation The enzymes responsible for methylating DNA, a ubiquitous epigenetic modification, have been extensively studied. Less is known about demethylation. Here, Tet1, an enzyme that catalyses the conversion of 5-methylcytosine of DNA to 5-hydroxyl-methylcytosine, is shown to have a role in mouse embryonic stem-cell maintenance by maintaining the expression of Nanog and preserving the Nanog promoter in a hypomethylated state. This suggests that Tet1 has a role in regulating DNA methylation, as well as in embryonic stem-cell self-renewal and inner cell mass specification. TET1 is an enzyme that catalyses the conversion of 5-methylcytosine of DNA to 5-hydroxymethylcytosine, raising the possibility that it is involved in mediating DNA demethylation. These authors show that Tet1 is involved in mouse embryonic stem cell maintenance and specification of the inner cell mass. It is required to maintain both the expression of Nanog in embryonic stem cells and the Nanog promoter in a hypomethylated state, supporting a role for Tet1 in regulating DNA methylation. DNA methylation is one of the best-characterized epigenetic modifications.sup.1,2,3,4. Although the enzymes that catalyse DNA methylation have been characterized, enzymes responsible for demethylation have been elusive.sup.5. A recent study indicates that the human TET1 protein could catalyse the conversion of 5-methylcytosine (5mC) of DNA to 5-hydroxymethylcytosine (5hmC), raising the possibility that DNA demethylation may be a Tet1-mediated process.sup.6. Here we extend this study by demonstrating that all three mouse Tet proteins (Tet1, Tet2 and Tet3) can also catalyse a similar reaction. Tet1 has an important role in mouse embryonic stem (ES) cell maintenance through maintaining the expression of Nanog in ES cells. Downregulation of Nanog via Tet1 knockdown correlates with methylation of the Nanog promoter, supporting a role for Tet1 in regulating DNA methylation status. Furthermore, knockdown of Tet1 in pre-implantation embryos results in a bias towards trophectoderm differentiation. Thus, our studies not only uncover the enzymatic activity of the Tet proteins, but also demonstrate a role for Tet1 in ES cell maintenance and inner cell mass cell specification.