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Inferring the three-dimensional structures of the X-chromosome during X-inactivation

1 Department of Computer Science, University of Miami, 1364 Memorial Drive, Coral Gables, FL 33124, USA
2 Department of Computer Science, New Jersey City University, 2039 Kennedy Blvd, Jersey City, NJ 07305, USA
3 Department of Computer Science, College of Charleston, Charleston, SC 29424, USA
4 Department of Physics and Astronomy, University of Southern Mississippi, 118 College Drive #5046, Hattiesburg, MS 39406, USA

Special Issues: Machine Learning in Molecular Biology

The Hi-C experiment can capture the genome-wide spatial proximities of the DNA, based on which it is possible to computationally reconstruct the three-dimensional (3D) structures of chromosomes. The transcripts of the long non-coding RNA (lncRNA) Xist spread throughout the entire X-chromosome and alter the 3D structure of the X-chromosome, which also inactivates one copy of the two X-chromosomes in a cell. The Hi-C experiments are expensive and time-consuming to conduct, but the Hi-C data of the active and inactive X-chromosomes are available. However, the Hi-C data of the X-chromosome during the process of X-chromosome inactivation (XCI) are not available. Therefore, the 3D structure of the X-chromosome during the process of X-chromosome inactivation (XCI) remains to be unknown. We have developed a new approach to reconstruct the 3D structure of the X-chromosome during XCI, in which the chain of DNA beads representing a chromosome is stored and simulated inside a 3D cubic lattice. A 2D Gaussian function is used to model the zero values in the 2D Hi-C contact matrices. By applying simulated annealing and Metropolis-Hastings simulations, we first generated the 3D structures of the X-chromosome before and after XCI. Then, we used Xist localization intensities on the X-chromosome (RAP data) to model the traveling speeds or acceleration between all bead pairs during the process of XCI. The 3D structures of the X-chromosome at 3 hours, 6 hours, and 24 hours after the start of the Xist expression, which initiates the XCI process, have been reconstructed. The source code and the reconstructed 3D structures of the X-chromosome can be downloaded from http://dna.cs.miami.edu/3D-XCI/.
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Keywords 3D genome; 3D cubic lattice; simulation; Xist; lncRNA; X-chromosome inactivation

Citation: Hao Zhu, Nan Wang, Jonathan Z. Sun, Ras B. Pandey, Zheng Wang. Inferring the three-dimensional structures of the X-chromosome during X-inactivation. Mathematical Biosciences and Engineering, 2019, 16(6): 7384-7404. doi: 10.3934/mbe.2019369


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