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Review
, 28 (12), 999-1013

The Role of Xist in X-Chromosome Dosage Compensation

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Review

The Role of Xist in X-Chromosome Dosage Compensation

Anna Sahakyan et al. Trends Cell Biol.

Abstract

In each somatic cell of a female mammal one X chromosome is transcriptionally silenced via X-chromosome inactivation (XCI), initiating early in development. Although XCI events are conserved in mouse and human postimplantation development, regulation of X-chromosome dosage in preimplantation development occurs differently. In preimplantation development, mouse embryos undergo imprinted form of XCI, yet humans lack imprinted XCI and instead regulate gene expression of both X chromosomes by dampening transcription. The long non-coding RNA Xist/XIST is expressed in mouse and human preimplantation and postimplantation development to orchestrate XCI, but its role in dampening is unclear. In this review, we discuss recent advances in our understanding of the role of Xist in X chromosome dosage compensation in mouse and human.

Keywords: X inactivation; Xist; dosage compensation; embryonic stem cells; lncRNAs.

Figures

Figure 1
Figure 1. X chromosome inactivation in different mammals
The X-chromosome states of eutherian (A and B) and metatherian (C) female mammals are shown in embryonic development. A) Imprinted XCI occurs in mouse pre-implantation development, but it is re-set in the cells that develop into the embryo to give way to random XCI, resulting in a mosaic adult female mouse. Both imprinted and random XCI in the mouse are regulated by the lncRNA Xist. B) Humans have evolved away from imprinted XCI as they dosage compensate in pre-implantation development by turning down transcription from both X chromosomes via XCD. Moreover, XIST is expressed on both dampened X chromosomes, where its functional role remains to be determined. In post-implantation development, similar to the mouse, human females display random XCI mediated by XIST. C) Metatherians, such as the marsupial opossum (Monodelphis domestica) dosage-compensate by inactivating the paternally-inherited X chromosome using the lncRNA Rsx. This imprinted dosage-compensation is maintained throughout marsupial development, resulting in a female adult with a transcriptionally inactive paternal X chromosome in all of its cells. XCI = X chromosome inactivation, Xist/XIST = X inactive specific transcript, Xa = active X chromosome, Xi = inactive X chromosome, Xm = maternal X chromosome, Xp = paternal X chromosome, XCD = X chromosome dampening, Rsx = RNA on the silent X.
Figure 2
Figure 2. Long non-coding RNAs involved in X chromosome dosage regulation in mouse and human
The X inactivation center (XIC) is located on the X chromosome and harbors the master regulator of XCI – the long non-coding RNA (lncRNA) Xist. A) In the mouse, Xist itself is positively regulated by the lncRNAs Jpx and Ftx, which are also encoded in the XIC, upstream of the Xist gene. The lncRNA Tsix, which is anti-sense to Xist, has a mutually exclusive expression pattern with Xist: it is expressed bi-allelically from both X chromosomes prior to XCI. Tsix ‘protects’ the active X chromosome in pluripotency from being silenced by Xist upon induction of XCI, and is thought to be a repressor of Xist. B) The human XIST gene is also encoded in the XIC of the human X chromosome. The lncRNAs JPX and FTX are also upstream of XIST in the human XIC, similar to mouse. The role of JPX and FTX in regulating XIST expression in human is speculated based on mouse studies. Unlike mouse, the human XIC does not contain the XIST anti-sense lncRNA TSIX, since TSIX expression is not detected in pre-implantation blastocysts or human embryonic stem cells. A novel, human-specific lncRNA, X active coating transcript (XACT), however, is encoded about 40Mb upstream of the human XIC and seems to antagonize XIST in naïve pluripotency. Similar to mouse Tsix, expression of XACT is unique to pluripotent cells and not detected in somatic cells.
Figure 3
Figure 3. Lack of Xist at various developmental time-points highlights its importance in normal development
Summary of key studies addressing the role of Xist in mouse development from fertilization to birth and into adulthood. (i) When a zygote is formed with a maternally deleted Xist (inherited from the egg), mouse development progresses normally and results in non-mosaic adults where all cells inactivate the paternally inherited X chromosome (since only that X has the only functional Xist allele). (ii) However, when Xist is deleted from both X chromosomes (from the egg and the sperm), or from only the paternal X chromosome (sperm), extra-embryonic tissues fail to develop in the absence of imprinted XCI since this process requires paternally-inherited Xist, and thus mouse development halts 5–7 days post implantation. (iii) Conditional Xist deletion from both X chromosomes in epiblast cells that give rise to the embryo is often embryonically lethal, and if pups are born, they display partial loss of X-chromosome silencing and do not survive to adulthood. (iv) When Xist is deleted several days post-implantation, specifically in hematopoietic stem cells (HSCs), after the establishment of the Xi, pups are born but succumb to Multilineage Dysplasia as early as 1.5 months after birth. E = embryonic day, Xist = X inactive specific transcript, iXCI = imprinted X-chromosome inactivation, HSCs = hematopoietic stem cells.
Figure 4
Figure 4. The X-chromosome state of naïve and primed human pluripotent stem cells
(i) Female human somatic cells have an active and an XIST-expressing inactive X chromosome (Xa and Xi). (ii) Reprogramming of these cells to primed pluripotency does not change the X-chromosome state. (iii) Similarly, derivation of hPSCs from a pre-implantation blastocyst stabilizes the post-XCI state in primed pluripotent culture conditions. (iv) Over time in culture, the Xi loses expression of XIST and undergoes epigenetic erosion, resulting in partial reactivation and thus double-dose of the X-linked genes that fall in these eroded regions in primed hPSCs. (v) Although these cells can differentiate into somatic lineages, the resulting differentiated cells maintain the eroded X (Xe). Female pre-implantation blastocysts have two active X chromosomes and express XIST, serving as a unique scenario where XIST expression does not cause XCI. (vi) When hESCs are derived under naïve pluripotent culture conditions, or when primed hPSCs are adapted to such naïve conditions, the X-chromosome state of resulting hPSCs resembles that of the pre-implantation blastocyst. (vii) Similar to normal development, differentiation of naïve hPSCs results in XIST-mediated XCI. *denotes the state found in majority of cells. hPSCs = human pluripotent stem cells, XIST = X inactive specific transcript, Xi = inactive X chromosome, Xa = active X chromosome, Xe = eroded X chromosome.

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