Dataset Information

Four-dimensional chromosome reconstruction elucidates the spatiotemporal reorganization of the mammalian X chromosome.

ABSTRACT: 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.

SUBMITTER: Lappala A

PROVIDER: S-EPMC8594586 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

Four-dimensional chromosome reconstruction elucidates the spatiotemporal reorganization of the mammalian X chromosome.

Lappala Anna A Wang Chen-Yu CY Kriz Andrea A Michalk Hunter H Tan Kevin K Lee Jeannie T JT Sanbonmatsu Karissa Y KY

Proceedings of the National Academy of Sciences of the United States of America 20211001 42

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 S ...[more]

PMID: 34645712

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Project description:Calculation of four-dimensional (4D) dose distributions requires the remapping of dose calculated on each available binned phase of the 4D CT onto a reference phase for summation. Deformable image registration (DIR) is usually used for this task, but unfortunately almost always considers only endpoints rather than the whole motion path. A new algorithm, 4D tissue deformation reconstruction (4D TDR), that uses either CT projection data or all available 4D CT images to reconstruct 4D motion data, was developed. The purpose of this work is to verify the accuracy of the fit of this new algorithm using a realistic tissue phantom. A previously described fresh tissue phantom with implanted electromagnetic tracking (EMT) fiducials was used for this experiment. The phantom was animated using a sinusoidal and a real patient-breathing signal. Four-dimensional computer tomography (4D CT) and EMT tracking were performed. Deformation reconstruction was conducted using the 4D TDR and a modified 4D TDR which takes real tissue hysteresis (4D TDR(Hysteresis)) into account. Deformation estimation results were compared to the EMT and 4D CT coordinate measurements. To eliminate the possibility of the high contrast markers driving the 4D TDR, a comparison was made using the original 4D CT data and data in which the fiducials were electronically masked. For the sinusoidal animation, the average deviation of the 4D TDR compared to the manually determined coordinates from 4D CT data was 1.9 mm, albeit with as large as 4.5 mm deviation. The 4D TDR calculation traces matched 95% of the EMT trace within 2.8 mm. The motion hysteresis generated by real tissue is not properly projected other than at endpoints of motion. Sinusoidal animation resulted in 95% of EMT measured locations to be within less than 1.2 mm of the measured 4D CT motion path, enabling accurate motion characterization of the tissue hysteresis. The 4D TDR(Hysteresis) calculation traces accounted well for the hysteresis and matched 95% of the EMT trace within 1.6 mm. An irregular (in amplitude and frequency) recorded patient trace applied to the same tissue resulted in 95% of the EMT trace points within less than 4.5 mm when compared to both the 4D CT and 4D TDR(Hysteresis) motion paths. The average deviation of 4D TDR(Hysteresis) compared to 4D CT datasets was 0.9 mm under regular sinusoidal and 1.0 mm under irregular patient trace animation. The EMT trace data fit to the 4D TDR(Hysteresis) was within 1.6 mm for sinusoidal and 4.5 mm for patient trace animation. While various algorithms have been validated for end-to-end accuracy, one can only be fully confident in the performance of a predictive algorithm if one looks at data along the full motion path. The 4D TDR, calculating the whole motion path rather than only phase- or endpoints, allows us to fully characterize the accuracy of a predictive algorithm, minimizing assumptions. This algorithm went one step further by allowing for the inclusion of tissue hysteresis effects, a real-world effect that is neglected when endpoint-only validation is performed. Our results show that the 4D TDR(Hysteresis) correctly models the deformation at the endpoints and any intermediate points along the motion path.

Dataset Information

Four-dimensional chromosome reconstruction elucidates the spatiotemporal reorganization of the mammalian X chromosome.

Publications

Four-dimensional chromosome reconstruction elucidates the spatiotemporal reorganization of the mammalian X chromosome.

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