Differentiation-dependent requirement of Tsix long non-coding RNA in imprinted X-chromosome inactivation

Maclary, Emily; Buttigieg, Emily; Hinten, Michael; Gayen, Srimonta; Harris, Clair; Sarkar, Mrinal K.; Purushothaman, Sonya; Kalantry, Sundeep

doi:10.1038/ncomms5209

Cited by 46 publications

(67 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[100][101][102][103][104][105][106][107][108] The LncRNAs may provide potential guides to complex with chromatinmodifying proteins and recruit their catalytic activity to specific sites in the genome, thereby modifying chromatin states and modulating gene expression. 109,110 For instance, lncRNA has functional links with PRC2, 110 and the direct interactions between PRC2 and RepA/Xist RNAs target PRC2 in cis to the mammalian X chromosome.…”

Section: Histone Modifications In Uterine Leiomyomamentioning

confidence: 99%

The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

et al. 2016

View full text Add to dashboard Cite

Uterine leiomyomas, also known as uterine fibroids, are the most common pelvic tumors, occurring in nearly 70% of all reproductive-aged women and are the leading indication for hysterectomy worldwide. The development of uterine leiomyomas involve a complex and heterogeneous constellation of hormones, growth factors, stem cells, genetic, and epigenetic abnormalities. An increasing body of evidence emphasizes the important contribution of epigenetics in the pathogenesis of leiomyomas. Genome-wide methylation analysis demonstrates that a subset of estrogen receptor (ER) response genes exhibit abnormal hypermethylation levels that are inversely correlated with their RNA expression. Several tumor suppressor genes, including Kruppel-like factor 11 (KLF11), deleted in lung and esophageal cancer 1 (DLEC1), keratin 19 (KRT19), and death-associated protein kinase 1 (DAPK1) also display higher hypermethylation levels in leiomyomas when compared to adjacent normal tissues. The important role of active DNA demethylation was recently identified with regard to the ten-eleven translocation protein 1 and teneleven translocation protein 3-mediated elevated levels of 5-hydroxymethylcytosine in leiomyoma. In addition, both histone deacetylase and histone methyltransferase are reported to be involved in the biology of leiomyomas. A number of deregulated microRNAs have been identified in leiomyomas, leading to an altered expression of their targets. More recently, the existence of side population (SP) cells with characteristics of tumor-initiating cells have been characterized in leiomyomas. These SP cells exhibit a tumorigenic capacity in immunodeficient mice when exposed to 17b-estradiol and progesterone, giving rise to fibroid-like tissue in vivo. These new findings will likely enhance our understanding of the crucial role epigenetics plays in the pathogenesis of uterine leiomyomas as well as point the way to novel therapeutic options.

show abstract

Section: Histone Modifications In Uterine Leiomyomamentioning

confidence: 99%

The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In addition to truncating Tsix transcription, the ΔTsix mutation deletes the critical DXPas34 repeat sequence close to the Xist-Tsix topological associated domain (TAD) boundary (30,31,(52)(53)(54)(55)(56). Consistent with the broadly coordinated regulation of genes within each of the two adjacent TADs, a 58-kb deletion encompassing the TAD boundary changes the transcription of multiple genes within the X-inactivation center (Xic) (33,57,58).…”

Section: δTsixmentioning

confidence: 90%

Sex-specific silencing of X-linked genes by Xist RNA

Gayen

Maclary

Hinten

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

X-inactive specific transcript (Xist) long noncoding RNA (lncRNA) is thought to catalyze silencing of X-linked genes in cis during X-chromosome inactivation, which equalizes X-linked gene dosage between male and female mammals. To test the impact of Xist RNA on X-linked gene silencing, we ectopically induced endogenous Xist by ablating the antisense repressor Tsix in mice. We find that ectopic Xist RNA induction and subsequent X-linked gene silencing is sex specific in embryos and in differentiating embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs). A higher frequency of X ΔTsix Y male cells displayed ectopic Xist RNA coating compared with X ΔTsix X female cells. This increase reflected the inability of X ΔTsix Y cells to efficiently silence X-linked genes compared with X ΔTsix X cells, despite equivalent Xist RNA induction and coating. Silencing of genes on both Xs resulted in significantly reduced proliferation and increased cell death in X ΔTsix X female cells relative to X ΔTsix Y male cells. Thus, whereas Xist RNA can inactivate the X chromosome in females it may not do so in males. We further found comparable silencing in differentiating X ΔTsix Y and 39,X ΔTsix (X ΔTsix O) ESCs, excluding the Y chromosome and instead implicating the X-chromosome dose as the source of the sexspecific differences. Because X ΔTsix X female embryonic epiblast cells and EpiSCs harbor an inactivated X chromosome prior to ectopic inactivation of the active X ΔTsix X chromosome, we propose that the increased expression of one or more X-inactivation escapees activates Xist and, separately, helps trigger X-linked gene silencing.inactivation represents a paradigm of epigenetic regulation and long noncoding RNA (lncRNA) function. In XX female cells, one of the two X chromosomes undergoes transcriptional silencing (1). Moreover, replicated copies of the active and inactive X chromosomes faithfully maintain their respective transcriptional states through many cell division cycles (2-5).X inactivation requires the X-inactive specific transcript (Xist) (6-8), a lncRNA that is selectively expressed from and physically coats the future inactive X chromosome (9-12). Xist RNA enables X-linked gene silencing by recruiting protein complexes to the inactive X (13-15). Female mouse embryos that inherit a paternal Xist mutation die due to defects in imprinted X inactivation of the paternal X chromosome in extraembryonic tissues (8,16,17). Xist is also required in the epiblast-derived embryonic cells, which undergo random X inactivation of either the maternal or the paternal X chromosome. Xist heterozygote fetal cells exhibit inactivation of only the X chromosome with an intact Xist locus, suggesting that Xist is necessary to choose the X chromosome to be inactivated (7,18,19). That the Xist-mutant X chromosome is not selected for inactivation, however, precludes assigning to Xist RNA a gene silencing role in the epiblast lineage.Ectopic expression studies have, however, demonstrated that Xist RNA can silence genes, albeit in a context-...

show abstract

“…Forced Tsix expression is sufficient to repress Xist precociously at earlier stages of development [105] and Tsix--mutant blastocysts show a delay in H3K27me3 erasure [47]. Therefore, albeit Tsix is not essential for XCR in the blastocyst [48], it appears to ensure the correct timing of the process, potentially by facilitating the binding of pluripotency factors like PRDM14 to Xist intron 1 [47].…”

Section: Resetting the Xci--stage By X--chromosome Reactivation (Xcr)mentioning

confidence: 99%

“…Tsix is expressed from the Xm during imprinted XCI and mouse embryos with a Tsix mutation on the Xm express Xist from both the paternal and maternal X--chromosomes in extraembryonic tissues and die during early postimplantation development [45,46]. During preimplantation stages, Tsix is not required for correct Xp--specific imprinted Xist expression [47,48], therefore its function for imprinted XCI seems to be mainly restricted to the extraembryonic tissues. DNA--methylation, which is essential for autosomal imprints, is not believed to play a major role in the maternal repressive imprint on Xist, as maternal deletion of the de novo DNA methyltransferase genes Dnmt3a and Dnmt3b does not interfere with imprinted XCI [49].…”

Section: Imprinted XCImentioning

confidence: 99%

Developmental regulation of X-chromosome inactivation

Payer

2016

Seminars in Cell & Developmental Biology

View full text Add to dashboard Cite

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.

show abstract

Differentiation-dependent requirement of Tsix long non-coding RNA in imprinted X-chromosome inactivation

Cited by 46 publications

References 56 publications

The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development

Sex-specific silencing of X-linked genes by Xist RNA

Developmental regulation of X-chromosome inactivation

Contact Info

Product

Resources

About