Abstract
BackgroundIn female mice, while the presence of two-active X-chromosomes characterises pluripotency, it is not tolerated in most other cellular contexts. In particular, in the trophoblastic lineage, impairment of paternal X (XP) inactivation results in placental defects.ResultsHere, we show that Trophoblast Stem (TS) cells can undergo a complete reversal of imprinted X-inactivation without detectable change in cell-type identity. This reversal occurs through a reactivation of the XP leading to TS clones showing two active Xs. Intriguingly, within such clones, all the cells rapidly and homogeneously either re-inactivate the XP or inactivate, de novo, the XM.ConclusionThis secondary non-random inactivation suggests that the two-active-X states in TS and in pluripotent contexts are epigenetically distinct. These observations also reveal a pronounced plasticity of the TS epigenome allowing TS cells to dramatically and accurately reprogram gene expression profiles. This plasticity may serve as a back-up system when X-linked mono-allelic gene expression is perturbed.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-015-0044-2) contains supplementary material, which is available to authorised users.
Highlights
In female mice, while the presence of two-active X-chromosomes characterises pluripotency, it is not tolerated in most other cellular contexts
X‐chromosome pre‐exist in undifferentiated populations of female Trophoblast Stem (TS) cells In order to evaluate the stability of imprinted X-chromosome inactivation (I-XCI) in undifferentiated TS cells, we used a female TS cell line (F3) carrying a mutation at the X-linked Hprt locus (Hprtbm1) associated with a retroviral insertion in the maternal Hprt1 gene, which leads to a stable loss-of-function of the maternal allele [28]
No HAT-resistant clones were observed in the time course of three independent experiments, indicating that the rate of [Hprt−] spontaneous reversal is very low in TS cells and will not significantly influence our results (Fig. 1b)
Summary
While the presence of two-active X-chromosomes characterises pluripotency, it is not tolerated in most other cellular contexts. The XY genotype results in the monoallelic expression of X-linked genes. In females, the presence of two X-chromosomes may lead to bi-allelic X-linked expression, which is known to be detrimental to the embryo [1]. To prevent this double dose of X-linked products, female mammals inactivate one X-chromosome. At the morula–blastocyst transition, the XP is reactivated in cells of the inner cell mass (ICM)—one of the two cell types known to be able to withstand two active Xs—while the inactivation of the XP persists in the extraembryonic
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