Dynamics of gene silencing during X inactivation using allele-specific RNA-seq

Marks, Hendrik; Kerstens, Hindrik H. D.; Barakat, Tahsin Stefan; Splinter, Erik; Dirks, René A.M.; Mierlo, Guido van; Joshi, Onkar; Wang, Shuang-Yin; Babak, Tomas; Albers, Cornelis A.; Kalkan, Tüzer; Smith, Austin; Jouneau, Alice; Laat, Wouter de; Gribnau, Joost; Stunnenberg, Hendrik G.

doi:10.1186/s13059-015-0698-x

Cited by 111 publications

(181 citation statements)

References 81 publications

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“…Transposition of a regulatory sensor into >1000 integration sites of the mouse genome illustrated this principle: Enhancers function within large regulatory domains that coincide with the TADs (Symmons et al 2014). In line with this, gene silencing on the inactive X chromosome in female mammalian cells was shown to also occur at the level of TADs, and gene clusters of escapees that do not become silenced correlate with TADs (Marks et al 2015). Further strong evidence for TADs being the functional units of the genome came from two recent studies that established the existence of the long-range impact of genetic variation on histone modifications elsewhere on chromosomes: Both studies showed that such communication takes place in the context of TADs (Grubert et al 2015;Waszak et al 2015).…”

Section: Tads and Sub-tadsmentioning

confidence: 57%

The second decade of 3C technologies: detailed insights into nuclear organization

2016

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The relevance of three-dimensional (3D) genome organization for transcriptional regulation and thereby for cellular fate at large is now widely accepted. Our understanding of the fascinating architecture underlying this function is based on microscopy studies as well as the chromosome conformation capture (3C) methods, which entered the stage at the beginning of the millennium. The first decade of 3C methods rendered unprecedented insights into genome topology. Here, we provide an update of developments and discoveries made over the more recent years. As we discuss, established and newly developed experimental and computational methods enabled identification of novel, functionally important chromosome structures. Regulatory and architectural chromatin loops throughout the genome are being cataloged and compared between cell types, revealing tissue invariant and developmentally dynamic loops. Architectural proteins shaping the genome were disclosed, and their mode of action is being uncovered. We explain how more detailed insights into the 3D genome increase our understanding of transcriptional regulation in development and misregulation in disease. Finally, to help researchers in choosing the approach best tailored for their specific research question, we explain the differences and commonalities between the various 3C-derived methods.

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Section: Tads and Sub-tadsmentioning

confidence: 57%

The second decade of 3C technologies: detailed insights into nuclear organization

2016

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“…As more tissues and cell samples have been evaluated and, as discussed above, definitions of XCI escape have been expanded to consider lower levels of inactive X expression, the number of variable escapees reported in mouse has increased to greater than 3% (figure 1a,b) [44,45,68,69]. Heterogeneity in inactive X expression levels can be seen within and between tissues types or cells, and even between mouse strains.…”

Section: (C) Sexual Dimorphismmentioning

confidence: 99%

When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome

Carrel

Brown

2017

Phil. Trans. R. Soc. B

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A tribute to Mary Lyon was held in October 2016. Many remarked about Lyon's foresight regarding many intricacies of the X-chromosome inactivation process. One such example is that a year after her original 1961 hypothesis she proposed that genes with Y homologues should escape from X inactivation to achieve dosage compensation between males and females. Fifty-five years later we have learned many details about these escapees that we attempt to summarize in this review, with a particular focus on recent findings. We now know that escapees are not rare, particularly on the human X, and that most lack functionally equivalent Y homologues, leading to their increasingly recognized role in sexually dimorphic traits. Newer sequencing technologies have expanded profiling of primary tissues that will better enable connections to sex-biased disorders as well as provide additional insights into the X-inactivation process. Chromosome organization, nuclear location and chromatin environments distinguish escapees from other X-inactivated genes. Nevertheless, several big questions remain, including what dictates their distinct epigenetic environment, the underlying basis of species differences in escapee regulation, how different classes of escapees are distinguished, and the roles that local sequences and chromosome ultrastructure play in escapee regulation.

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“…Most X-linked genes in females with an inactive X chromosome are expressed at levels equal to that in males (73)(74)(75). A subset of X-linked genes, however, escape X inactivation in female cells and are capable of being expressed from both X chromosomes despite inactivation of one of the two Xs (76,77). Due to expression from both alleles, these X-inactivation escapees are expressed at higher levels in females compared with males (78).…”

Section: δTsixmentioning

confidence: 99%

“…Recent reports of proteins bound to Xist found two X-encoded proteins, NONO and RBM3, as direct Xist RNA partners (14,15). Neither gene, however, escapes random X inactivation (77,78). The critical escapee proteins may therefore only indirectly or transiently interact with Xist, or may indirectly induce Xist and X-linked gene silencing.…”

Section: δTsixmentioning

confidence: 99%

“…The Xic, however, may not be sufficient to recapitulate the various steps underlying random X inactivation, including the sensing of the X-chromosomal dose, as suggested by the inability of large single-copy YAC Xic transgenes to induce Xist (28,29). A recent report delineating X-inactivation escapees in ESCs via allele-specific RNA-seq may yield candidate X-inactivation regulators (77). It is also plausible that the escapees indirectly control Xist induction and gene silencing by up-regulating the active allele of a gene(s) that is subject to X inactivation, inducing other escapees, or triggering the sexspecific expression of autosomal factors.…”

Section: δTsixmentioning

confidence: 99%

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

Gayen

Maclary

Hinten

et al. 2016

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

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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-...

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Dynamics of gene silencing during X inactivation using allele-specific RNA-seq

Cited by 111 publications

References 81 publications

The second decade of 3C technologies: detailed insights into nuclear organization

The second decade of 3C technologies: detailed insights into nuclear organization

When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome

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

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