The lesser known story of X-chromosome reactivation: A closer look into the reprogramming of the inactive X chromosome

X-chromosome inactivation (XCI) is an important mechanism employed by mammalian XX female cells to level X-linked gene expression with that of male XY cells. XCI occurs early in development as the pluripotent cells of the inner cell mass (ICM) in blastocysts successively differentiate into cells of all three germ layers. X-chromosome reactivation (XCR), the reversal of XCI, is critical for germ cell formation as a mechanism to diversify the X-chromosome gene pool. Here we review the characterization of XCR, and further explore its natural occurrence during development and the in vitro models of cellular reprogramming. We also review the key regulators involved in XCI for their role in suppressing the active histone marks and the genes in the active chromosome for their inhibition of X inactivation signals.Key words: X-chromosome reactivation, RNF12, reprogramming, primordial germ cells, iPS cellsX-chromosome inactivation (XCI) is an essential process occurring in female XX cells as a dosage compensation measure during development.¹ It ensures balanced X-chromosome-encoded proteins in male and female cells, and occurs randomly during early development, thus accounting for the mosaicism observed in female somatic cells. Once the cell has inactivated one of the X chromosomes, the pattern is maintained throughout the subsequent series of cell divisions. In mice, the paternal inactive X chromosome (Xi) is maintained throughout the early cleavage until the blastocyst stage, where cells of the inner cell mass (ICM) reactivate the inactive X chromosome.² At subsequent phases of early development, humans and mice share the pattern of XCI. Epiblast cells randomly inactivate one X chromosome, while the primordial germ cells (PGCs) reactivate the Xi during their migration to the genital ridges.^3–6 Interestingly, murine extra-embryonic trophoblast cells show non-random inactivation of the paternal X chromosome maintained in trophectoderm.^6,7 This pattern is, however, not conserved, as human trophectoderm cells randomly inactivate the paternal or maternal X chromosome. In addition to the PGCs and early developing embryo, cells cultured under defined conditions or undergoing reprogramming show X-chromosome reactivation (XCR).⁸ XCI has been extensively studied, while XCR is not well-understood, mainly due to the lack of easily accessible models. Here, we will review the developmental process of XCR and molecular mechanism involved in XCI and XCR.