Recent Advances in Understanding the Reversal of Gene Silencing During X Chromosome Reactivation

Talón, Irene; Janiszewski, Adrian; Chappell, Joel; Vanheer, Lotte; Pasque, Vincent

doi:10.3389/fcell.2019.00169

Cited by 22 publications

(14 citation statements)

References 143 publications

(236 reference statements)

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“…During this process, Xist repels architectural proteins like CTCF and Cohesin (Minajigi et al, 2015), thereby actively contributing to the attenuation of TADs (Wang et al, 2018) and leading to he Xi di inc chromo ome conforma ion (Colognori et al, 2019;Giorgetti et al, 2016;Splinter et al, 2011). There has been intense research effort to understand the dynamics of transcriptional silencing, the mechanisms of transition to the unique structure of the Xi and the connection between the two processes (Froberg et al, 2018;Gdula et al, 2019;Wang et al, 2018Wang et al, , 2019, but how the process is reversed during the reactivation of the X chromosome has received attention only recently (Cantone and Fisher, 2017;Payer, 2016;Talon et al, 2019).…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…During this process, Xist repels architectural proteins like CTCF and Cohesin 11 , thereby actively contributing to the attenuation of TADs 8 and leading to the distinct chromosome conformation 7,17,18 of the Xi. There has been intense research effort to understand the dynamics of transcriptional silencing, the mechanisms of transition to the unique structure of the Xi and the connection between the two processes 8,9,19,20 , but how the process is reversed during the reactivation of the X chromosome has received attention only recently 1,21,22 .…”

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confidence: 99%

Chromosome compartments on the inactive X guide TAD formation independently of transcription during X-reactivation

et al. 2021

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A 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 to be absent from the inactive mouse 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 a time course combining gene reactivation, chromatin opening and chromosome topology during X-reactivation. Contrary to previous observations, we observe A/B-like compartments on the inactive X harbouring multiple subcompartments. While partial X-reactivation initiates within a compartment rich in X-inactivation escapees, it then occurs rapidly along the chromosome, concomitant with downregulation of Xist. Importantly, we find that TAD formation precedes transcription and initiates from Xist-poor compartments. Here, we show that TAD formation and transcriptional reactivation are causally independent during X-reactivation while establishing Xist as a common denominator.

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“…Despite its importance, much less is known about XCR compared with XCI. In contrast to XCI, XCR leads to the silencing of Xist, increased expression of antisense lncRNA Tsix, loss of repressive chromatin marks, recruitment of active chromatin modifications, and subsequent chromosomewide gene reactivation (Pasque and Plath 2015;Talon et al 2019). Previous studies during mouse development have shown that the reversal of iXCI is a gradual process over 24 h. XCR initiates before the loss of Xist and is partially restricted by H3K27me3, which is actively removed by KDM6A (also known as UTX) H3K27 histone demethylase in order to activate slowly reactivating genes (Borensztein et al 2017a).…”

mentioning

confidence: 99%

Dynamic reversal of random X-Chromosome inactivation during iPSC reprogramming

et al. 2019

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Induction and reversal of chromatin silencing is critical for successful development, tissue homeostasis, and the derivation of induced pluripotent stem cells (iPSCs). X-Chromosome inactivation (XCI) and reactivation (XCR) in female cells represent chromosome-wide transitions between active and inactive chromatin states. Although XCI has long been studied, providing important insights into gene regulation, the dynamics and mechanisms underlying the reversal of stable chromatin silencing of X-linked genes are much less understood. Here, we use allele-specific transcriptomics to study XCR during mouse iPSC reprogramming in order to elucidate the timing and mechanisms of chromosome-wide reversal of gene silencing. We show that XCR is hierarchical, with subsets of genes reactivating early, late, and very late during reprogramming. Early genes are activated before the onset of late pluripotency genes activation. Early genes are located genomically closer to genes that escape XCI, unlike genes reactivating late. Early genes also show increased pluripotency transcription factor (TF) binding. We also reveal that histone deacetylases (HDACs) restrict XCR in reprogramming intermediates and that the severe hypoacetylation state of the inactive X Chromosome (Xi) persists until late reprogramming stages. Altogether, these results reveal the timing of transcriptional activation of monoallelically repressed genes during iPSC reprogramming, and suggest that allelic activation involves the combined action of chromatin topology, pluripotency TFs, and chromatin regulators. These findings are important for our understanding of gene silencing, maintenance of cell identity, reprogramming, and disease.

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Recent Advances in Understanding the Reversal of Gene Silencing During X Chromosome Reactivation

Cited by 22 publications

References 143 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

Chromosome compartments on the inactive X guide TAD formation independently of transcription during X-reactivation

Dynamic reversal of random X-Chromosome inactivation during iPSC reprogramming

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