Dataset Information

Forged by DXZ4, FIRRE, and ICCE: How Tandem Repeats Shape the Active and Inactive X Chromosome.

ABSTRACT: Recent efforts in mapping spatial genome organization have revealed three evocative and conserved structural features of the inactive X in female mammals. First, the chromosomal conformation of the inactive X reveals a loss of topologically associated domains (TADs) present on the active X. Second, the macrosatellite DXZ4 emerges as a singular boundary that suppresses physical interactions between two large TAD-depleted "megadomains." Third, DXZ4 reaches across several megabases to form "superloops" with two other X-linked tandem repeats, FIRRE and ICCE, which also loop to each other. Although all three structural features are conserved across rodents and primates, deletion of mouse and human orthologs of DXZ4 and FIRRE from the inactive X have revealed limited impact on X chromosome inactivation (XCI) and escape in vitro. In contrast, loss of Xist or SMCHD1 have been shown to impair TAD erasure and gene silencing on the inactive X. In this perspective, we summarize these results in the context of new research describing disruption of X-linked tandem repeats in vivo, and discuss their possible molecular roles through the lens of evolutionary conservation and clinical genetics. As a null hypothesis, we consider whether the conservation of some structural features on the inactive X may reflect selection for X-linked tandem repeats on account of necessary cis- and trans-regulatory roles they may play on the active X, rather than the inactive X. Additional hypotheses invoking a role for X-linked tandem repeats on X reactivation, for example in the germline or totipotency, remain to be assessed in multiple developmental models spanning mammalian evolution.

SUBMITTER: Bansal P

PROVIDER: S-EPMC6985041 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Forged by DXZ4, FIRRE, and ICCE: How Tandem Repeats Shape the Active and Inactive X Chromosome.

Bansal Prakhar P Kondaveeti Yuvabharath Y Pinter Stefan F SF

Frontiers in cell and developmental biology 20200121

Recent efforts in mapping spatial genome organization have revealed three evocative and conserved structural features of the inactive X in female mammals. First, the chromosomal conformation of the inactive X reveals a loss of topologically associated domains (TADs) present on the active X. Second, the macrosatellite DXZ4 emerges as a singular boundary that suppresses physical interactions between two large TAD-depleted "megadomains." Third, DXZ4 reaches across several megabases to ...[more]

PMID: 32076600

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Project description:During interphase, the inactive X chromosome (Xi) adopts an unusual 3D configuration known as the Barr body and is largely transcriptionally silent. Despite the importance of X inactivation, little is known about the 3D configuration of Xi and its relationship to gene silencing. We recently showed that in humans, Xi exhibits two distinctive structural features. First, Xi is partitioned into two huge intervals, called superdomains, such that pairs of loci in each superdomain show an enhanced contact frequency with one another. The boundary between the two superdomains lies near DXZ4, a macrosatellite repeat spanning ~300kb, whose Xi allele extensively binds the protein CTCF. Second, Xi exhibits extremely large loops, up to 77Mb long, called superloops. DXZ4 lies at the anchor of several superloops. Here, we use 3D mapping to study the structure of Xi, focusing on the role of DXZ4. We show that superloops and superdomains are conserved across mammals. We develop a novel variant of our in situ Hi-C protocol, dubbed COLA (COncatemer Ligation Assay) to probe the higher order structures formed by the superloops. In COLA, in situ proximity ligation of multiple extremely short fragments produced by the enzyme CviJI is used to efficiently map simultaneous proximity among three or more loci. Using data from Hi-C and COLA, we demonstrate that DXZ4 and other superloop anchors tend to co-locate simultaneously within the same cells, a result that is confirmed by 3D-FISH. Finally, we examine the effects of deleting DXZ4 from Xi in human cells. Using in situ Hi-C, microscopy, and RNA-FISH, we show that superdomains and superloops disappear; that Xi frequently dissociates into multiple separate structures; and that transcriptional silencing on Xi is compromised. Deletion of DXZ4 from the active X chromosome (Xa) has no such effect. Thus, DXZ4 is essential for proper folding and silencing of Xi. Hi-C protocol was used on wildtype and DXZ4-deleted cells to examine the structure of Xi. A novel variant of our in situ Hi-C protocol, dubbed COLA (COncatemer Ligation Assay), was developed to probe the higher order structures formed by the superloops. This series also includes RNA-seq data on Retinal Pigmented Epithelial Cells (hTERT-RPE1). At the time of submission, processed data were available only for the RNA-seq samples. Submitter states that processed data files for HiC samples will be added to this series in the future.

Dataset Information

Forged by DXZ4, FIRRE, and ICCE: How Tandem Repeats Shape the Active and Inactive X Chromosome.

Publications

Forged by <i>DXZ4</i>, <i>FIRRE</i>, and <i>ICCE</i>: How Tandem Repeats Shape the Active and Inactive X Chromosome.

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