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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 the sharp megadomain border, whereas deleting
Firre
weakens intra-megadomain interactions. However, deleting
Dxz4
and/or
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. We conclude that
Dxz4
and megadomains are dispensable for Xi silencing and escape from X-inactivation.
The mammalian inactive X-chromosome (Xi) is organized into megadomains and superloops directed by the noncoding loci,
Dxz4
and
Firre
. Here the authors provide evidence that megadomains do not precede
Xist
expression or Xi gene silencing, and suggest that
Dxz4
,
Firre
, and megadomains are dispensable for Xi silencing and escape from X-inactivation.