The macrosatellite DXZ4 mediates CTCF-dependent long-range intrachromosomal interactions on the human inactive X chromosome

Horáková, Andrea Harničarová; Moseley, Shawn C.; McLaughlin, Christine R; Tremblay, Deanna C.; Chadwick, Brian P.

doi:10.1093/hmg/dds270

Cited by 72 publications

(100 citation statements)

References 57 publications

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“…Both the second and third loci have complex tandem repeat structures, and all three include annotated piRNAs, which are known to have vital sex-specific roles in germline cells (Girard et al 2006). Interestingly, these two loci were identified in a recent independent study as having intense H3K4me2 signals on the metaphase X chromosome (Horakova et al 2012). Each locus was also implicated in inactive-X-specific long-range interactions supporting a role in sex specificity.…”

Section: Resultsmentioning

confidence: 99%

Patterns of regulatory activity across diverse human cell types predict tissue identity, transcription factor binding, and long-range interactions

et al. 2013

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Regulatory elements recruit transcription factors that modulate gene expression distinctly across cell types, but the relationships among these remains elusive. To address this, we analyzed matched DNase-seq and gene expression data for 112 human samples representing 72 cell types. We first defined more than 1800 clusters of DNase I hypersensitive sites (DHSs) with similar tissue specificity of DNase-seq signal patterns. We then used these to uncover distinct associations between DHSs and promoters, CpG islands, conserved elements, and transcription factor motif enrichment. Motif analysis within clusters identified known and novel motifs in cell-type-specific and ubiquitous regulatory elements and supports a role for AP-1 regulating open chromatin. We developed a classifier that accurately predicts cell-type lineage based on only 43 DHSs and evaluated the tissue of origin for cancer cell types. A similar classifier identified three sex-specific loci on the X chromosome, including the XIST lincRNA locus. By correlating DNase I signal and gene expression, we predicted regulated genes for more than 500K DHSs. Finally, we introduce a web resource to enable researchers to use these results to explore these regulatory patterns and better understand how expression is modulated within and across human cell types.

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Section: Resultsmentioning

confidence: 99%

Patterns of regulatory activity across diverse human cell types predict tissue identity, transcription factor binding, and long-range interactions

et al. 2013

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“…The affected genes are distributed across the length of the X chromosome (Fig. 6B); interestingly, a cluster of 11 reactivated genes is located adjacent to the macrosatellite locus DXZ4, a boundary that separates two large megadomains of the Xi (15,36,37).…”

Section: Discussionmentioning

confidence: 99%

A high-throughput small molecule screen identifies synergism between DNA methylation and Aurora kinase pathways for X reactivation

Lessing

Dial

Wei

et al. 2016

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

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X-chromosome inactivation is a mechanism of dosage compensation in which one of the two X chromosomes in female mammals is transcriptionally silenced. Once established, silencing of the inactive X (Xi) is robust and difficult to reverse pharmacologically. However, the Xi is a reservoir of >1,000 functional genes that could be potentially tapped to treat X-linked disease. To identify compounds that could reactivate the Xi, here we screened ∼367,000 small molecules in an automated high-content screen using an Xi-linked GFP reporter in mouse fibroblasts. Given the robust nature of silencing, we sensitized the screen by “priming” cells with the DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (5azadC). Compounds that elicited GFP activity include VX680, MLN8237, and 5azadC, which are known to target the Aurora kinase and DNA methylation pathways. We demonstrate that the combinations of VX680 and 5azadC, as well as MLN8237 and 5azadC, synergistically up-regulate genes on the Xi. Thus, our work identifies a synergism between the DNA methylation and Aurora kinase pathways as being one of interest for possible pharmacological reactivation of the Xi.

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“…We also showed that the macrosatellite element DXZ4 (11-13) is situated at the boundary of the superdomains (10) and is bound by CCCTC-binding factor (CTCF) exclusively on the Xi homolog (14). DXZ4 also lies at the anchor of superloops to XIST, FIRRE, LOC550643 (which we here dub the "inactive-X CTCF-binding contact element," ICCE), and to a previously uncharacterized locus at ChrX:75350000-75400000 (which we refer to here as "x75") (10,15).…”

mentioning

confidence: 99%

Deletion of DXZ4 on the human inactive X chromosome alters higher-order genome architecture

Darrow

Huntley

Dudchenko

et al. 2016

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

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During interphase, the inactive X chromosome (Xi) is largely transcriptionally silent and adopts an unusual 3D configuration known as the "Barr body." Despite the importance of X chromosome inactivation, little is known about this 3D conformation. We recently showed that in humans the Xi chromosome exhibits three structural features, two of which are not shared by other chromosomes. First, like the chromosomes of many species, Xi forms compartments. Second, Xi is partitioned into two huge intervals, called "superdomains," such that pairs of loci in the same superdomain tend to colocalize. The boundary between the superdomains lies near DXZ4, a macrosatellite repeat whose Xi allele extensively binds the protein CCCTC-binding factor. Third, Xi exhibits extremely large loops, up to 77 megabases long, called "superloops." DXZ4 lies at the anchor of several superloops. Here, we combine 3D mapping, microscopy, and genome editing to study the structure of Xi, focusing on the role of DXZ4. We show that superloops and superdomains are conserved across eutherian mammals. By analyzing ligation events involving three or more loci, we demonstrate that DXZ4 and other superloop anchors tend to colocate simultaneously. Finally, we show that deleting DXZ4 on Xi leads to the disappearance of superdomains and superloops, changes in compartmentalization patterns, and changes in the distribution of chromatin marks. Thus, DXZ4 is essential for proper Xi packaging.

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The macrosatellite DXZ4 mediates CTCF-dependent long-range intrachromosomal interactions on the human inactive X chromosome

Cited by 72 publications

References 57 publications

Patterns of regulatory activity across diverse human cell types predict tissue identity, transcription factor binding, and long-range interactions

Patterns of regulatory activity across diverse human cell types predict tissue identity, transcription factor binding, and long-range interactions

A high-throughput small molecule screen identifies synergism between DNA methylation and Aurora kinase pathways for X reactivation

Deletion of DXZ4 on the human inactive X chromosome alters higher-order genome architecture

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