Establishment of X chromosome inactivation and epigenomic features of the inactive X depend on cellular contexts

Abstract

Establishment of X chromosome inactivation and epigenomic features of the inactive X depend on cellular contexts C eline Vallot, Jean-François Ouimette and Claire Rougeulle à X chromosome inactivation (XCI) is an essential epigenetic process that ensures X-linked gene dosage equilibrium between sexes in mammals. XCI is dynamically regulated during development in a manner that is intimately linked to differentiation. Numerous studies, which we review here, have explored the dynamics of X inactivation and reactivation in the context of development, differentiation and diseases, and the phenotypic and molecular link between the inactive status, and the cellular context. Here, we also assess whether XCI is a uniform mechanism in mammals by analyzing epigenetic signatures of the inactive X (Xi) in different species and cellular contexts. It appears that the timing of XCI and the epigenetic signature of the inactive X greatly vary between species. Surprisingly, even within a given species, various Xi configurations are found across cellular states. We discuss possible mechanisms underlying these variations, and how they might influence the fate of the Xi.Keywords:.d evelopment; differentiation; heterochromatin landscape; non-coding RNA; pluripotency; stem cells; X chromosome inactivation IntroductionDosage disequilibrium introduced by the heteromorphic nature of the X and Y sex chromosomes is compensated by mechanisms that specifically target the X chromosome and modulate its transcriptional competency. The first hint of male/female chromatin difference in mammals was cytological evidence of a nuclear body specific to female somatic cells, referred to as the Barr body [1], and identified as a condensed X chromosome [2]. The formation of this sex chromatin was proposed by Mary Lyon to arise early during development and to result in the transcriptional silencing of one the two Xs, in females only [3]. Balancing X-linked gene products in females through X chromosome inactivation (XCI) is essential for proper development, and failure to do so blocks embryogenesis shortly after implantation [4,5]. In adults, presence of two active X (Xa) chromosomes in somatic cells has been observed mainly in deleterious cell states such as cancer cells [6,7], and loss of X-linked gene dosage compensation is believed to cause aggressive hematological cancers [8]. XCI is triggered by chromosome-wide coating of the long non-coding RNA (lncRNA) Xist and characterized by profound changes of the epigenetic landscape of the inactive X chromosome (Xi) with respect to its active counterpart. Molecular events downstream of XIST accumulation and leading to stable silencing include eviction of RNA polymerases, accumulation of specific histones modifications and

New Advances in Human X Chromosome Status from a Developmental and Stem Cell Biology

“…Nanog, Oct4, and Sox2 mark the naïve state and collectively repress the ubiquitin ligase Rnf12 (21) that lies in the Xist TAD (17), prior to dosage compensation. As naïve state TFs become depleted, Rnf12 is activated and marks Rex1 for degradation (21). Rex1 is another naïve TF that, along with KLF4 and c-Myc, activates the lncRNA Tsix (21).…”

“…As naïve state TFs become depleted, Rnf12 is activated and marks Rex1 for degradation (21). Rex1 is another naïve TF that, along with KLF4 and c-Myc, activates the lncRNA Tsix (21). Tsix is the key repressor of Xist function in mice and negatively regulates Xist expression in cis (17).…”

“…Tsix is the key repressor of Xist function in mice and negatively regulates Xist expression in cis (17). On the active X chromosome, the Xite element in the Tsix TAD promotes the expression of Tsix in cis (17, 21), in turn generating Tsix expression asymmetry(22), facilitating the inactivation of the Tsix-null X chromosome. However, the process of this transition from biallelic to monoallelic Tsix expression has not been fully explained.…”

Deciphering the Role of the Barr Body in Malignancy: An insight into head and neck cancer

“…20 Variations in Xi frequency have been reported with age, pregnancy, the use of oral contraceptives, fluctuations in menstrual cycle and neoplasia. [21][22][23][24][25] Moore et al found that the frequency of the sex chromatin in the nuclei of female hosts was low in malignant tissues, appearing in only about one-third of tumours in comparison to non-malignant tissues; this finding was attributed to the diverse chromosomal abnormalities that occur in malignancy.…”

“…34,35 The misexpression of XIST may potentially be a mechanism underlying oncogenesis and low XIST levels may reduce X inactivation with continuous X reactivation. 20 However, the molecular cascade that alters X inactivation and X chromosome copy numbers in both female and male cancer cells remains undetermined.…”