Microscopic Chromosomal Structural and Dynamical Origin of Cell Differentiation and Reprogramming

Chu, Xiakun; Wang, Jin

doi:10.1002/advs.202001572

Cited by 19 publications

(24 citation statements)

References 98 publications

(164 reference statements)

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“…expression, epigenetics and 3D genome architecture [3][4][5], the non-monotonic transitions in chromosome structure should also be expected during the reprogramming. With a landscapeswitching model, we observed the over-expanding chromosome structures, which are more open than those at the fibroblast and ES cells, during the reprogramming, resonating with the experimental evidence [45]. Here, we found that the chromosome during cell cancerization opens its structure and partially forms the structure, similar to the one formed in the ES cell.…”

Section: Plos Computational Biologysupporting

confidence: 80%

“…The pathways are projected onto (A) the extensions of the longest and the shortest principal axes (PA1 and PA3), (B) the radius of gyration ( R g ) and the aspheric quantity (Δ), contact similarity in terms of the fraction of native contact Q to the IMR90 and A549 at (C) local range (0–2Mb), and (D) long-range (10–15Mb). The data of the ES cell are obtained from our previous work [ 45 ].…”

Section: Resultsmentioning

confidence: 99%

“…In the end, the chromosome under the potential V(r|S) generates an ensemble that can reproduce the Hi-C maps at the normal and cancer cell, separately (S1 Fig) . Details of the maximum entropy principle simulation can be found in previous studies [72,73]. The maximum entropy principles simulations for the ES and IMR90 cells were done in our previous work [45].…”

Section: Maximum Entropy Principle Simulationmentioning

confidence: 99%

“…First, we applied the maximum entropy principle to incorporate the Hi-C data of the normal and cancer cells into two independent sets of simulations. These simulations generated two potentials for describing the chromosome structural ensembles that reproduced the Hi-C data, in the normal and cancer cells, respectively ( S1 and S2 Figs) [ 45 ]. In the cell nucleus, the chromosome constantly experiences the nonequilibrium effects even at one cell state, leading to a nonequilibrium system.…”

Section: Introductionmentioning

confidence: 99%

“…To bridge these two landscapes for describing transitions between the normal and cancer cells, we then used a landscape-switching model, which was developed to simulate the chromosome structural transition during the cell cycle [ 53 ] and the cell developmental processes [ 45 ]. Briefly, the chromosome structural dynamics at either normal or cancer cell was initially described by an effective equilibrium landscape generated by the data-driven maximum entropy principle simulation.…”

Section: Introductionmentioning

confidence: 99%

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Deciphering the molecular mechanism of the cancer formation by chromosome structural dynamics

Chu

Wang

2021

PLoS Comput Biol

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Cancer reflects the dysregulation of the underlying gene network, which is strongly related to the 3D genome organization. Numerous efforts have been spent on experimental characterizations of the structural alterations in cancer genomes. However, there is still a lack of genomic structural-level understanding of the temporal dynamics for cancer initiation and progression. Here, we use a landscape-switching model to investigate the chromosome structural transition during the cancerization and reversion processes. We find that the chromosome undergoes a non-monotonic structural shape-changing pathway with initial expansion followed by compaction during both of these processes. Furthermore, our analysis reveals that the chromosome with a more expanding structure than those at both the normal and cancer cell during cancerization exhibits a sparse contact pattern, which shows significant structural similarity to the one at the embryonic stem cell in many aspects, including the trend of contact probability declining with the genomic distance, the global structural shape geometry and the spatial distribution of loci on the chromosome. In light of the intimate structure-function relationship at the chromosomal level, we further describe the cell state transition processes by the chromosome structural changes, suggesting an elevated cell stemness during the formation of the cancer cells. We show that cell cancerization and reversion are highly irreversible processes in terms of the chromosome structural transition pathways, spatial repositioning of chromosomal loci and hysteresis loop of contact evolution analysis. Our model draws a molecular-scale picture of cell cancerization from the chromosome structural perspective. The process contains initial reprogramming towards the stem cell followed by the differentiation towards the cancer cell, accompanied by an initial increase and subsequent decrease of the cell stemness.

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Section: Plos Computational Biologysupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Maximum Entropy Principle Simulationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deciphering the molecular mechanism of the cancer formation by chromosome structural dynamics

Chu

Wang

2021

PLoS Comput Biol

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Uncovering the Quantitative Relationships Among Chromosome Fluctuations, Epigenetics, and Gene Expressions of Transdifferentiation on Waddington Landscape

Chu

Wang

2022

Advanced Science

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The 3D spatial organization of the chromosomes appears to be linked to the gene function, which is cell type-specific. The chromosome structural ensemble switching model (CSESM) is developed by employing a heteropolymer model on different cell types and the important quantitative relationships among the chromosome ensemble, the epigenetic marks, and the gene expressions are uncovered, that both chromosome fluctuation and epigenetic marks have strong linear correlations with the gene expressions. The results support that the two compartments have different behaviors, corresponding to the relatively sparse and fluctuating phase (compartment A) and the relatively dense and stable phase (compartment B). Importantly, through the investigation of the transdifferentiation processes between the peripheral blood mononuclear cell (PBMC) and the bipolar neuron (BN), a quantitative description for the transdifferentiation is provided, which can be linked to the Waddington landscape. In addition, compared to the direct transdifferentiation between PBMC and BN, the transdifferentiation via the intermediate state neural progenitor cell (NPC) follows a different path (an "uphill" followed by a "downhill"). These theoretical studies bridge the gap among the chromosome fluctuations/ensembles, the epigenetics, and gene expressions in determining the cell fate.

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Three‐dimensional genome structure and function

Líu

Tsai

Yang

et al. 2023

MedComm

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Linear DNA undergoes a series of compression and folding events, forming various three‐dimensional (3D) structural units in mammalian cells, including chromosomal territory, compartment, topologically associating domain, and chromatin loop. These structures play crucial roles in regulating gene expression, cell differentiation, and disease progression. Deciphering the principles underlying 3D genome folding and the molecular mechanisms governing cell fate determination remains a challenge. With advancements in high‐throughput sequencing and imaging techniques, the hierarchical organization and functional roles of higher‐order chromatin structures have been gradually illuminated. This review systematically discussed the structural hierarchy of the 3D genome, the effects and mechanisms of cis‐regulatory elements interaction in the 3D genome for regulating spatiotemporally specific gene expression, the roles and mechanisms of dynamic changes in 3D chromatin conformation during embryonic development, and the pathological mechanisms of diseases such as congenital developmental abnormalities and cancer, which are attributed to alterations in 3D genome organization and aberrations in key structural proteins. Finally, prospects were made for the research about 3D genome structure, function, and genetic intervention, and the roles in disease development, prevention, and treatment, which may offer some clues for precise diagnosis and treatment of related diseases.

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Microscopic Chromosomal Structural and Dynamical Origin of Cell Differentiation and Reprogramming

Cited by 19 publications

References 98 publications

Deciphering the molecular mechanism of the cancer formation by chromosome structural dynamics

Deciphering the molecular mechanism of the cancer formation by chromosome structural dynamics

Uncovering the Quantitative Relationships Among Chromosome Fluctuations, Epigenetics, and Gene Expressions of Transdifferentiation on Waddington Landscape

Three‐dimensional genome structure and function

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