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Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4504-12. doi: 10.1073/pnas.1609643113. Epub 2016 Jul 18.

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

Author information

1
Department of Biological Science, Florida State University, Tallahassee, FL 32306;
2
The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030; John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138; Broad Institute of MIT and Harvard, Cambridge, MA 02139;
3
The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030; Center for Theoretical Biological Physics, Rice University, Houston, TX 77030;
4
The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030; Broad Institute of MIT and Harvard, Cambridge, MA 02139;
5
The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030;
6
The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030; Center for Theoretical Biological Physics, Rice University, Houston, TX 77030; Department of Computer Science, Stanford University, Stanford, CA 94305;
7
Broad Institute of MIT and Harvard, Cambridge, MA 02139; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Systems Biology, Harvard Medical School, Boston, MA 02115; erez@erez.com lander@broadinstitute.org chadwick@bio.fsu.edu.
8
Department of Biological Science, Florida State University, Tallahassee, FL 32306; erez@erez.com lander@broadinstitute.org chadwick@bio.fsu.edu.
9
The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030; Broad Institute of MIT and Harvard, Cambridge, MA 02139; Center for Theoretical Biological Physics, Rice University, Houston, TX 77030; Department of Computer Science, Rice University, Houston, TX 77005; Department of Computational and Applied Mathematics, Rice University, Houston, TX 77005 erez@erez.com lander@broadinstitute.org chadwick@bio.fsu.edu.

Abstract

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.

KEYWORDS:

CTCF; Hi‐C; X chromosome inactivation; genome engineering; inactive X chromosome

PMID:
27432957
PMCID:
PMC4978254
DOI:
10.1073/pnas.1609643113
[Indexed for MEDLINE]
Free PMC Article

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