Coupling of X-Chromosome reactivation with the pluripotent stem cell state

Payer, Bernhard; Lee, Jeannie T.

doi:10.4161/rna.29779

Cited by 34 publications

(41 citation statements)

References 110 publications

(173 reference statements)

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“…[46,57] It has been proposed that the process of XCI itself may substantially alter the availability and composition of epigenetic complexes in female relative to male cells ( Figure 2b). XCI is a massive epigenetic event that has broad effects on the transcriptome of the cell and is intimately tied to differentiation.…”

Section: Female Cells Undergo X Chromosome Inactivation (Xci)mentioning

confidence: 99%

Sex Differences in Early Embryogenesis: Inter‐Chromosomal Regulation Sets the Stage for Sex‐Biased Gene Networks

Engel

2018

BioEssays

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Sex-specific transcriptional and epigenomic profiles are detectable in the embryo very soon after fertilization. I propose that in male (XY) and female (XX) pre-implantation embryos sex chromosomes establish sexually dimorphic interactions with the autosomes, before overt differences become apparent and long before gonadogenesis. Lineage determination restricts expression biases between the sexes, but the epigenetic differences are less constrained and can be perpetuated, accounting for dimorphisms that arise later in life. In this way, sexual identity is registered in the epigenome very early in development. As development progresses, sex-specific regulatory modules are harbored within shared transcriptional networks that delineate common traits. In reviewing this field, I propose that analyzing the mechanisms for sexual dimorphisms at the molecular and biochemical level and incorporating developmental and environmental factors will lead to a greater understanding of sex differences in health and disease. Also see the video abstract here: https://youtu.be/9BPlbrHtkHQ.

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Section: Female Cells Undergo X Chromosome Inactivation (Xci)mentioning

confidence: 99%

Sex Differences in Early Embryogenesis: Inter‐Chromosomal Regulation Sets the Stage for Sex‐Biased Gene Networks

Engel

2018

BioEssays

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“…While X--dosage affects differentiation, the pluripotent state inhibits XCI [10,11,77,78] and this inhibition is released during differentiation. This feedback of the cell differentiation state on XCI regulation is directly controlled by pluripotency--associated transcription factors, which bind along the Xic in multiple locations.…”

Section: Random XCI -A Hallmark Of Cell Differentiationmentioning

confidence: 99%

“…XCI is a tightly controlled, multilayered epigenetic event essential for mouse development [6], and defects in XCI maintenance are associated with cancer in mice and humans [7--9]. XCI is not a permanent state, as it is reversed in the mouse embryo by X--chromosome reactivation (XCR), which occurs in the pluripotent epiblast and in the germ cell lineage [10,11]. In vitro, XCR is associated with mouse pluripotent stem cells like embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs).…”

Section: Introductionmentioning

confidence: 99%

“…XCI and XCR are thereby linked to differentiation and pluripotency, respectively, and the molecular intertwining between X--chromosome dosage compensation and the cellular differentiation state is recently becoming increasingly uncovered. At the core of XCI/XCR regulation lies the X--inactivation center (Xic), which is a locus on the X--chromosome containing a number of mostly non--coding RNA genes, the expression of which is controlled by pluripotency factors [10]. The most prominent long non--coding RNA at the Xic is Xist (X--inactive specific transcript), which is expressed only from the future inactive X--chromosome (Xi), which Xist coats and silences in cis [12--15].…”

Section: Introductionmentioning

confidence: 99%

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Developmental regulation of X-chromosome inactivation

Payer

2016

Seminars in Cell & Developmental Biology

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With the emergence of sex--determination by sex chromosomes, which differ in composition and number between males and females, appeared the need to equalize X--chromosomal gene dosage between the sexes. Mammals have devised the strategy of X--chromosome inactivation (XCI), in which one of the two X--chromosomes is rendered transcriptionally silent in females. In the mouse, the best--studied model organism with respect to XCI, this inactivation process occurs in different forms, imprinted and random, interspersed by periods of X--chromosome reactivation (XCR), which is needed to switch between the different modes of XCI. In this review, I describe the recent advances with respect to the developmental control of XCI and XCR and in particular their link to differentiation and pluripotency. Furthermore, I review the mechanisms, which influence the timing and choice, with which one of the two X--chromosomes is chosen for inactivation during random XCI. This has an impact on how females are mosaics with regard to which X--chromosome is active in different cells, which has implications on the severity of diseases caused by X--linked mutations.

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“…Once XCI is established, Tsix is only transcribed at low level from the Xa. Additional repressors of Xist expression include the pluripotency factors, such as SOX2, OCT4, NANOG, and PRDM14, which prevent XCI in undifferentiated ESCs [13] . Down-regulation of the pluripotent factors precedes the initiation of XCI.…”

Section: Introductionmentioning

confidence: 99%

Novel molecular players of X chromosome inactivation: new technologies and new insights

Przanowski¹,

Wasko²,

Bhatnagar³

2018

JTGG

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The dosage compensation in placental mammals is achieved by silencing of one copy of the X chromosomes in a female cell by a process called X chromosome inactivation (XCI). XCI ensures equal gene dosage for X-linked genes between the two genders. Although the choice of X chromosome to be silenced is random, once the silencing of the X chromosome has been established, this process is highly regulated and maintained throughout subsequent cell divisions. A long non-coding RNA, Xist , and its interacting proteins execute this multistep process, but several of these regulatory proteins remain unidentified. Recent technological advances based on the genetic and proteomics screening have identified several new regulatory factors as well as dissected the molecular details of XCI regulation. Moreover, identification of regulators of XCI offers an opportunity to explore reactivation of the inactive X chromosome (Xi ) as a potential therapeutic strategy to treat X-linked diseases, like Rett syndrome. Here, we summarize recent reports that identified new regulatory proteins and RNA species playing a crucial role in Xist localization and spreading, recruitment of silencing machinery to the Xi , Xist interaction with chromatin, and structural organization of the Xi in the nuclei.

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Coupling of X-Chromosome reactivation with the pluripotent stem cell state

Cited by 34 publications

References 110 publications

Sex Differences in Early Embryogenesis: Inter‐Chromosomal Regulation Sets the Stage for Sex‐Biased Gene Networks

Sex Differences in Early Embryogenesis: Inter‐Chromosomal Regulation Sets the Stage for Sex‐Biased Gene Networks

Developmental regulation of X-chromosome inactivation

Novel molecular players of X chromosome inactivation: new technologies and new insights

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