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Megadomains and superloops form dynamically but are dispensable for X-chromosome inactivation and gene escape

John E. Froberg, Stefan F. Pinter, Andrea J. Kriz, Teddy Jégu, Jeannie T. Lee
doi: https://doi.org/10.1101/364893
John E. Froberg
1Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
2Department of Genetics, Harvard Medical School, Boston, MA, US
3Howard Hughes Medical Institute
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Stefan F. Pinter
1Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
2Department of Genetics, Harvard Medical School, Boston, MA, US
3Howard Hughes Medical Institute
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Andrea J. Kriz
1Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
2Department of Genetics, Harvard Medical School, Boston, MA, US
3Howard Hughes Medical Institute
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Teddy Jégu
1Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
2Department of Genetics, Harvard Medical School, Boston, MA, US
3Howard Hughes Medical Institute
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Jeannie T. Lee
1Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
2Department of Genetics, Harvard Medical School, Boston, MA, US
3Howard Hughes Medical Institute
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  • For correspondence: lee@molbio.mgh.harvard.edu
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ABSTRACT

The mammalian inactive X-chromosome (Xi) is structurally distinct from all other chromosomes and serves as a model for how the 3D genome is organized. The Xi shows weakened topologically associated domains and is instead organized into megadomains and superloops directed by the noncoding loci, Dxz4 and Firre. Their functional significance is presently unclear, though one study suggests that they permit Xi genes to escape silencing. Here, we find that megadomains do not precede Xist expression or Xi gene silencing. Deleting Dxz4 disrupts megadomain formation, whereas deleting Firre weakens intra-megadomain interactions. Surprisingly, however, deleting Dxz4 and Firre has no impact on Xi silencing and gene escape. Nor does it affect Xi nuclear localization, stability, or H3K27 methylation. Additionally, ectopic integration of Dxz4 and Xist is not sufficient to form megadomains on autosomes, further uncoupling megadomain formation from chromosomal silencing. We conclude that Dxz4 and megadomains are dispensable for Xi silencing and escape from X-inactivation.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted July 08, 2018.
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Megadomains and superloops form dynamically but are dispensable for X-chromosome inactivation and gene escape
John E. Froberg, Stefan F. Pinter, Andrea J. Kriz, Teddy Jégu, Jeannie T. Lee
bioRxiv 364893; doi: https://doi.org/10.1101/364893
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Megadomains and superloops form dynamically but are dispensable for X-chromosome inactivation and gene escape
John E. Froberg, Stefan F. Pinter, Andrea J. Kriz, Teddy Jégu, Jeannie T. Lee
bioRxiv 364893; doi: https://doi.org/10.1101/364893

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