X–chromosome inactivation during differentiation of female teratocarcinoma stem cells in vitro

Martin, Gail R.; Epstein, Charles J.; Travis, Bruce; Tucker, Georgianne; Yatziv, S; Martin, David W.; Clift, Shirley M.; Cohen, Sara

doi:10.1038/271329a0

Cited by 127 publications

(42 citation statements)

References 29 publications

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“…Fitting for this meeting though, was the fact that no in vitro model existed for this process before the derivation of EC cell lines. Using a female teratocarcinoma cell line, Gail Martin (Martin et al, 1978) revealed X-chromosome inactivation during differentiation, a finding later confirmed in mouse ES cells. However, it should be noted that this is considered the second 'random' wave of X-inactivation.…”

Section: Characterisation Of Pluripotent Cellsmentioning

confidence: 79%

Rediscovering pluripotency: from teratocarcinomas to embryonic stem cells

Barbaric¹,

Harrison²

2012

Int. J. Dev. Biol.

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The pluripotent potential of embryonic stem cells has often seen them touted as the future of regenerative medicine. The road to any therapeutic success however, must stretch back to teratocarcinoma, the tumour from which pluripotent stem cells (embryonal carcinoma cells) were first derived. This 2011 meeting in Cardiff acted as a historical perspective from which the impact of embryonal carcinoma cell research on the present pluripotent stem cell landscape could be observed, with many of the early luminaries in this field still very active. The meeting addressed the genetic and epigenetic make-up of pluripotent stem cells, the mechanisms which control their fate, and their relationship to the early embryo proper. With each speaker tasked with revisiting previous questions, this meeting demonstrated how far has been travelled, yet how far is left to go.

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Section: Characterisation Of Pluripotent Cellsmentioning

confidence: 79%

Rediscovering pluripotency: from teratocarcinomas to embryonic stem cells

Barbaric¹,

Harrison²

2012

Int. J. Dev. Biol.

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“…Thus, although the normal differentiation of the X chromosome requires its inactivation rather than activation (27), the induction of HPRT synthesis in the highly-selectable HAT system should allow us to address further questions to the control of cellular differentiation through the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Cell cycle-specific reactivation of an inactive X-chromosome locus by 5-azadeoxycytidine.

Jones¹,

Taylor²,

Mohandas³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

132

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Three cytidine analogs containing modifications in the 5-position of the cytosine ring (5-azacytidine, 5-aza-2'-deoxycytidine and pseudoisocytidine) induced the expression of human hypoxanthine/guanine phosphoribosyltransferase (IMP: pyrophosphate phosphoribosyltransferase, EC 2.4.2.8) gene (HPRT) from a structurally normal inactive human X chromosome retained in a mouse-human somatic cell hybrid. Between 0.1% and 8% of the cells surviving treatment with these analogs were able to form colonies in selective medium (hypoxanthine/aminopterin/thymidine/glycine medium), but two other analogs, 5-fluoro-2'-deoxycytidine and 5,6-dihydro-5-azacytidine, did not induce HPRT expression. The inactive X chromosome present in the hybrid, was found to be late replicating, and experiments with synchronized cells showed that the induction of HPRT expression by 5-aza-2'-deoxycytidine occurred maximally in.cells treated in the latter half of the S phase. Two division cycles were required after analog treatment for the highest frequency of expression of the induced gene. Because these analogs are powerful inhibitors of the methylation of cytosine residues in DNA, the results imply that demethylation of specific DNA sequences may be required for the reexpression of human HPRT.The successful passage through the S phase in the eukaryotic cell cycle requires not only the accurate replication ofthe genotype but also the faithful copying of the cellular phenotype.

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“…Phosphoglycerate kinase (PGK), glucose-6-phosphate dehydrogenase (G6PD), and HPRT isozyme analyses were performed with cell lysates prepared as previously described (19). Electrophoretic separations were performed with Cellogel (Kalex Scientific).…”

mentioning

confidence: 99%

Methylation of the mouse hprt gene differs on the active and inactive X chromosomes.

Lock¹,

Melton²,

Caskey³

et al. 1986

Mol. Cell. Biol.

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It has been proposed that DNA methylation is involved in the mechanism of X inactivation, the process by which equivalence of levels of X-linked gene products is achieved in female (XX) and male (XY) mammals. In this study, Southern blots of female and male DNA digested with methylation-sensitive restriction endonucleases and hybridized to various portions of the cloned mouse hprt gene were compared, and sites within the mouse hprt gene were identified that are differentially methylated in female and male cells. The extent to which these sites are methylated when carried on the active and inactive X chromosomes was directly determined in a similar analysis of DNA from clonal cel lines established from a female embryo derived from a mating of two species of mouse, Mus musculus and Mus caroli. The results revealed two regions of differential methylation in the mouse hprt gene. One region, in the first intron of the gene, includes four sites that are completely unmethylated when carried on the active X and extensively methylated when carried on the inactive X. These same sites are extensively demethylated in hprt genes reactivated either spontaneously or after 5-azacytidine treatment. The second region includes several sites in the 3' 20kilobases of the gene extending from exon 3 to exon 9 that show the converse pattern; i.e., they are completely methylated when carried on the active X and completely unmethylated when carried on the inactive X. At least one of these sites does not become methylated after reactivation of the gene. The results of this study, together with the results of previous studies by others of the human hprt gene, indicate that these regions of differential methylation on the active and inactive X are conserved between mammalian species. Furthermore, the data described here are consistent with the idea that at least the sites in the 5' region of the gene play a role in the X inactivation phenomenon and regulation of expression of the mouse hprt gene.In mammals, female and male cells express equivalent levels of most X-linked gene products despite the fact that females have twice the number of X-linked genes per diploid complement as do ma-les. This "dosage compensation" of X-linked genes in mammals results from the inactivation of one of the two X chromosomes in each female cell (16) concomitant with cellular differentiation in the early embryo (24,25,32). Once it is established, inactivity of the X chromosome is stably inherited through successive mitotic divisions. In germ cells, however, the inactive X is reactivated just prior to meiosis (4,8,12). X chromosome inactivation and reactivation thus represent stable changes in gene expression that are developmentally regulated.The mechanisms by which X inactivation and reactivation occur are unknown, but it has been suggested that X inactivation occurs in several phases, i.e., the primary inactivation event, spreading of inactivation from the site(s) of the initial event, and a process that results in maintenance of the inactive state. It has be...

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X–chromosome inactivation during differentiation of female teratocarcinoma stem cells in vitro

Abstract: Evidence is presented that both X chromosomes are genetically active in clonal cultures of undifferentiated female mouse teratocarcinoma stem cells derived from a spontaneous ovarian tumour. As the cells differentiate in vitro one of the X chromosomes becomes inactivated.

Cited by 127 publications

References 29 publications

Rediscovering pluripotency: from teratocarcinomas to embryonic stem cells

Rediscovering pluripotency: from teratocarcinomas to embryonic stem cells

Cell cycle-specific reactivation of an inactive X-chromosome locus by 5-azadeoxycytidine.

Methylation of the mouse hprt gene differs on the active and inactive X chromosomes.

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