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Dynamics and Pathways of Chromosome Structural Organizations during Cell Transdifferentiation

[Image: see text] Direct conversion of one differentiated cell type into another is defined as cell transdifferentiation. In avoidance of forming pluripotency, cell transdifferentiation can reduce the potential risk of tumorigenicity, thus offering significant advantages over cell reprogramming in c...

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Autores principales: Chu, Xiakun, Wang, Jin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8791059/
https://www.ncbi.nlm.nih.gov/pubmed/35098228
http://dx.doi.org/10.1021/jacsau.1c00416
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author Chu, Xiakun
Wang, Jin
author_facet Chu, Xiakun
Wang, Jin
author_sort Chu, Xiakun
collection PubMed
description [Image: see text] Direct conversion of one differentiated cell type into another is defined as cell transdifferentiation. In avoidance of forming pluripotency, cell transdifferentiation can reduce the potential risk of tumorigenicity, thus offering significant advantages over cell reprogramming in clinical applications. Until now, the mechanism of cell transdifferentiation is still largely unknown. It has been well recognized that cell transdifferentiation is determined by the underlying gene expression regulation, which relies on the accurate adaptation of the chromosome structure. To dissect the transdifferentiation at the molecular level, we develop a nonequilibrium landscape-switching model to investigate the chromosome structural dynamics during the state transitions between the human fibroblast and neuron cells. We uncover the high irreversibility of the transdifferentiation at the local chromosome structural ranges, where the topologically associating domains form. In contrast, the pathways in the two opposite directions of the transdifferentiation projected onto the chromosome compartment profiles are highly overlapped, indicating that the reversibility vanishes at the long-range chromosome structures. By calculating the contact strengths in the chromosome at the states along the paths, we observe strengthening contacts in compartment A concomitant with weakening contacts in compartment B at the early stages of the transdifferentiation. This further leads to adapting contacts toward the ones at the embryonic stem cell. In light of the intimate structure–function relationship at the chromosomal level, we suggest an increase of “stemness” during the transdifferentiation. In addition, we find that the neuron progenitor cell (NPC), a cell developmental state, is located on the transdifferentiation pathways projected onto the long-range chromosome contacts. The findings are consistent with the previous single-cell RNA sequencing experiment, where the NPC-like cell states were observed during the direct conversion of the fibroblast to neuron cells. Thus, we offer a promising microscopic and physical approach to study the cell transdifferentiation mechanism from the chromosome structural perspective.
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spelling pubmed-87910592022-01-27 Dynamics and Pathways of Chromosome Structural Organizations during Cell Transdifferentiation Chu, Xiakun Wang, Jin JACS Au [Image: see text] Direct conversion of one differentiated cell type into another is defined as cell transdifferentiation. In avoidance of forming pluripotency, cell transdifferentiation can reduce the potential risk of tumorigenicity, thus offering significant advantages over cell reprogramming in clinical applications. Until now, the mechanism of cell transdifferentiation is still largely unknown. It has been well recognized that cell transdifferentiation is determined by the underlying gene expression regulation, which relies on the accurate adaptation of the chromosome structure. To dissect the transdifferentiation at the molecular level, we develop a nonequilibrium landscape-switching model to investigate the chromosome structural dynamics during the state transitions between the human fibroblast and neuron cells. We uncover the high irreversibility of the transdifferentiation at the local chromosome structural ranges, where the topologically associating domains form. In contrast, the pathways in the two opposite directions of the transdifferentiation projected onto the chromosome compartment profiles are highly overlapped, indicating that the reversibility vanishes at the long-range chromosome structures. By calculating the contact strengths in the chromosome at the states along the paths, we observe strengthening contacts in compartment A concomitant with weakening contacts in compartment B at the early stages of the transdifferentiation. This further leads to adapting contacts toward the ones at the embryonic stem cell. In light of the intimate structure–function relationship at the chromosomal level, we suggest an increase of “stemness” during the transdifferentiation. In addition, we find that the neuron progenitor cell (NPC), a cell developmental state, is located on the transdifferentiation pathways projected onto the long-range chromosome contacts. The findings are consistent with the previous single-cell RNA sequencing experiment, where the NPC-like cell states were observed during the direct conversion of the fibroblast to neuron cells. Thus, we offer a promising microscopic and physical approach to study the cell transdifferentiation mechanism from the chromosome structural perspective. American Chemical Society 2021-12-09 /pmc/articles/PMC8791059/ /pubmed/35098228 http://dx.doi.org/10.1021/jacsau.1c00416 Text en © 2021 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Chu, Xiakun
Wang, Jin
Dynamics and Pathways of Chromosome Structural Organizations during Cell Transdifferentiation
title Dynamics and Pathways of Chromosome Structural Organizations during Cell Transdifferentiation
title_full Dynamics and Pathways of Chromosome Structural Organizations during Cell Transdifferentiation
title_fullStr Dynamics and Pathways of Chromosome Structural Organizations during Cell Transdifferentiation
title_full_unstemmed Dynamics and Pathways of Chromosome Structural Organizations during Cell Transdifferentiation
title_short Dynamics and Pathways of Chromosome Structural Organizations during Cell Transdifferentiation
title_sort dynamics and pathways of chromosome structural organizations during cell transdifferentiation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8791059/
https://www.ncbi.nlm.nih.gov/pubmed/35098228
http://dx.doi.org/10.1021/jacsau.1c00416
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AT wangjin dynamicsandpathwaysofchromosomestructuralorganizationsduringcelltransdifferentiation