Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 42, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2107092118
Keywords
X chromosome inactivation; Xist RNA; chromosome structure; 3D modeling; SMCHD1
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Funding
- Los Alamos National Laboratory (LANL) Laboratory Directed Research and Development [20210082DR]
- LANL Laboratory Directed Research and Development grant [20210134ER, F31HD100109-01]
- NIH [R01-HD097665]
- LANL Institutional Computing
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This study developed tools to directly extract 3D information from Hi-C experiments, revealing the time evolution of chromosome architecture during large-scale changes in gene expression. The X chromosome transitions through different structures during X chromosome inactivation, showing slow mixing dynamics in the inner core and faster dynamics near the surface. Xist RNA molecules play a role in establishing the inactive X chromosome structure.
Chromosomes are segmented into domains and compartments, but how these structures are spatially related in three dimensions (3D) is unclear. Here, we developed tools that directly extract 3D information from Hi-C experiments and integrate the data across time. With our 4DHiC method, we use X chromosome inactivation (XCI) as a model to examine the time evolution of 3D chromosome architecture during large-scale changes in gene expression. Our modeling resulted in several insights. Both A/B and S1/S2 compartments divide the X chromosome into hemisphere-like structures suggestive of a spatial phase-separation. During the XCI, the X chromosome transits through A/B, S1/S2, and megadomain structures by undergoing only partial mixing to assume new structures. Interestingly, when an active X chromosome (Xa) is reorganized into an inactive X chromosome (Xi), original underlying compartment structures are not fully eliminated within the Xi superstructure. Our study affirms slow mixing dynamics in the inner chromosome core and faster dynamics near the surface where escapees reside. Once established, the Xa and Xi resemble glassy polymers where mixing no longer occurs. Finally, Xist RNA molecules initially reside within the A compartment but transition to the interface between the A and B hemispheres and then spread between hemispheres via both surface and core to establish the Xi.
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