A Conserved Noncoding Locus Regulates Random Monoallelic Xist Expression across a Topological Boundary

Galupa, Rafael; Nora, Elphège P.; Worsley-Hunt, Rebecca; Picard, Christel; Gard, Chris; Bemmel, Joke G. van; Servant, Nicolas; Zhan, Yinxiu; Marjou, Fatima El; Johanneau, Colin; Diabangouaya, Patricia; Saux, Agnès Le; Lameiras, Sonia; Fonseca, Juliana Pipoli da; Loos, Friedemann; Gribnau, Joost; Baulande, Sylvain; Ohler, Uwe; Giorgetti, Luca; Heard, Edith

doi:10.1016/j.molcel.2019.10.030

Cited by 55 publications

(82 citation statements)

References 113 publications

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“…Next, we investigated the regulatory landscape of the Xic from a structural perspective. The Xic is divided into two functionally opposing domains (van Bemmel et al, 2019;Galupa et al, 2020;Nora et al, 2012;Spencer et al, 2011;Tsai et al, 2008): TAD-D, which contains the noncoding genes Tsix, Xite and Linx, which are repressors of Xist; and TAD-E, which harbors Xist itself and its activators, the non-coding Jpx and Ftx and the protein-coding Rlim/Rnf12 ( Figure 5C). First, we noticed a gradual strengthening of the TAD border between TAD-D and TAD-E during reprogramming, as indicated by a drop in the insulation score ( Figure 5C).…”

Section: Remodeling Of the X-inactivation Center Leads To Xist Downrementioning

confidence: 99%

Chromosome Compartments on the Inactive X Guide TAD Formation Independently of Transcription during X-Reactivation

Bauer

Vidal

Zorita

et al. 2020

Preprint

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SummaryA hallmark of chromosome organization is the partition into transcriptionally active A and repressed B compartments and into topologically associating domains (TADs). Both structures were regarded absent from the inactive X chromosome, but to be re-established with transcriptional reactivation and chromatin opening during X-reactivation. Here, we combine a tailor-made mouse iPSC-reprogramming system and high-resolution Hi-C to produce the first time-course combining gene reactivation, chromatin opening and chromosome topology during X-reactivation. Contrary to previous observations, we uncover A/B-like compartments on the inactive X harboring multiple subcompartments. While partial X-reactivation initiates within a compartment rich in X-inactivation escapees, it then occurs rapidly along the chromosome, coinciding with acquisition of naive pluripotency, leading to downregulation of Xist. Importantly, we find that TAD formation precedes transcription, suggesting them to be causally independent. Instead, TADs form first within Xist-poor compartments, establishing Xist as common denominator, opposing both gene reactivation and TAD formation through separate mechanisms.Graphical Summary

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Section: Remodeling Of the X-inactivation Center Leads To Xist Downrementioning

confidence: 99%

Chromosome Compartments on the Inactive X Guide TAD Formation Independently of Transcription during X-Reactivation

Bauer

Vidal

Zorita

et al. 2020

Preprint

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“…The mechanism by which hundreds of genes are repressed in a coordinated manner has captured the interest of researchers for over half a century but is by no means the only aspect of the mammalian dosage compensation system that remains a puzzling wonder of biology 1 . The choice of the X chromosome to switch off, either maternal or paternal, is widely accepted to be random in placental mammals, and recent evidence in mice suggests a stochastic process for which a few components have been identified 2,3 . A mechanism for generating randomness is difficult to establish on a molecular basis but ultimately may inspire technology as well as cell biology.…”

Section: Introductionmentioning

confidence: 99%

The B-side of Xist

Monfort

Wutz

2020

F1000Res

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Female mammals express the long noncoding X inactivation-specific transcript (Xist) RNA to initiate X chromosome inactivation (XCI) that eventually results in the formation of the Barr body. Xist encompasses half a dozen repeated sequence stretches containing motifs for RNA-binding proteins that recruit effector complexes with functions for silencing genes and establishing a repressive chromatin configuration. Functional characterization of these effector proteins unveils the cooperation of a number of pathways to repress genes on the inactive X chromosome. Mechanistic insights can be extended to other noncoding RNAs with similar structure and open avenues for the design of new therapies to switch off gene expression. Here we review recent advances in the understanding of Xist and on this basis try to synthesize a model for the initiation of XCI.

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“…A recent study identified another potential and evolutionarily conserved modulator of Xist, called Linx. The report highlights the contextual role played by Linx as a silencer of Xist when in its original location in Tsix TAD and as an enhancer when artificially placed in Xist TAD (Galupa et al, 2020) The conserved cRE identified in mouse is actually designated as the P2 promoter that has been demonstrated to bind YY1 and CTCF (Johnston et al, 1998;Makhlouf et al, 2014;Navarro et al, 2006;Sun et al, 2013). As opposed to our observation of female-specific enrichment of CTCF in mouse (Xi) (Fig.…”

Section: Discussionmentioning

confidence: 97%

“…However, when it is placed in Xist TAD, it serves as an enhancer of Xist (Galupa et al, 2020). Besides the X-chromosomal cis-acting modulators, the autosomally encoded trans-acting factors such as the core pluripotency factors -Oct4, Sox2, Nanog, Klf4 and c-Myc link the two developmental events of differentiation and XCI (Schulz et al, 2014), by regulating Xist (Navarro et al, 2008;Nesterova et al, 2011), Tsix (Donohoe et al, 2009;Navarro et al, 2010) and Rnf12 (Navarro et al, 2011), Linx (Galupa et al, 2020). Thus, it can be convincingly stated that Xist expression is robustly regulated by a multitude of cis and trans factors acting either synergistically or independently to ensure accurate execution of the developmentally important process of XCI.…”

Section: Introductionmentioning

confidence: 99%

A novel cis regulatory element regulates human XIST in CTCF-dependent manner

Shah

Kelkar²,

Galande³

2019

Preprint

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The long non-coding RNA XIST is the master regulator for the process of X chromosome inactivation in mammalian females. Here we report the existence of a hitherto uncharacterized cis regulatory element within the first exon of human XIST, which by associating with the promoter region through chromatin looping defines the transcriptional status of XIST. This interaction is brought about by CTCF, which in turn assists towards the maintenance of YY1 binding at the promoter and governs XIST transcription. Strikingly, the cis element is competitively bound by pluripotency factors and CTCF, wherein the enrichment of the former disrupts its interaction with thepromoter, leading to downregulation of XIST. Based on sequence similarity of this element across species we propose that this mechanism is conserved between the human and mouse systems. Collectively, our study uncovers the

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A Conserved Noncoding Locus Regulates Random Monoallelic Xist Expression across a Topological Boundary

Cited by 55 publications

References 113 publications

Chromosome Compartments on the Inactive X Guide TAD Formation Independently of Transcription during X-Reactivation

Chromosome Compartments on the Inactive X Guide TAD Formation Independently of Transcription during X-Reactivation

The B-side of Xist

A novel cis regulatory element regulates human XIST in CTCF-dependent manner

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