Chemo-Mechanical Cues Modulate Nano-Scale Chromatin Organization in Healthy and Diseased Connective Tissue Cells

Heo, Sook-Kyoung; Thakur, Satbir; Chen, X; Loebel, Claudia; Xia, Bao‐Hui; McBeath, Rowena; Ja, Burdick; Vb, Shenoy; Mauck, RL; Lakadamyali, Melike

doi:10.1101/2021.04.27.441596

Cited by 7 publications

(6 citation statements)

References 69 publications

(125 reference statements)

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“…In Heo et al, 2021 , the authors developed a field-based model simulating HC formation which incorporates the kinetics of methylation and acetylation in order to clarify the impact of the changes in histone methylation status on chromatin condensation. They found that the methylation/acetylation reactions lead to interconversion of the EC and HC phases, and it provides more HC-EC interfaces.…”

Section: Discussionmentioning

confidence: 99%

How enzymatic activity is involved in chromatin organization

Das

Sakaue

Shivashankar

et al. 2022

eLife

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Spatial organization of chromatin plays a critical role in genome regulation. Previously, various types of affnity mediators and enzymes have been attributed to regulate spatial organization of chromatin from a thermodynamics perspective. However, at the mechanistic level, enzymes act in their unique ways and perturb the chromatin. Here, we construct a polymer physics model following the mechanistic scheme of Topoisomerase-II, an enzyme resolving topological constraints of chromatin, and investigate how it affects interphase chromatin organization. Our computer simulations demonstrate Topoisomerase-II's ability to phase separate chromatin into eu- and heterochromatic regions with a characteristic wall-like organization of the euchromatic regions. We realized that the ability of the euchromatic regions to cross each other due to enzymatic activity of Topoisomerase-II induces this phase separation. This realization is based on the physical fact that partial absence of self-avoiding interaction can induce phase separation of a system into its self-avoiding and non-self-avoiding parts, which we reveal using a mean-field argument. Furthermore, motivated from recent experimental observations, we extend our model to a bidisperse setting and show that the characteristic features of the enzymatic activity driven phase separation survive there. The existence of these robust characteristic features, even under the non-localized action of the enzyme, highlights the critical role of enzymatic activity in chromatin organization.

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Section: Discussionmentioning

confidence: 99%

How enzymatic activity is involved in chromatin organization

Das

Sakaue

Shivashankar

et al. 2022

eLife

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“…Conversely, extracellular physical forces can also affect nuclear mechanics and chromosome structure. Mechanical cues in a cell's environment can lead to a spatial redistribution of chromatin (preprint: Heo et al , 2021). Irreversible stretching of chromatin domains has been observed in some nuclei aspirated into narrow micropipettes (Irianto et al , 2017b), and external cellular forces can even affect gene expression through direct chromatin deformations (Tajik et al , 2016).…”

Section: Introductionmentioning

confidence: 99%

Constricted migration is associated with stable 3D genome structure differences in cancer cells

et al. 2022

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To spread from a localized tumor, metastatic cancer cells must squeeze through constrictions that cause major nuclear deformations. Since chromosome structure affects nucleus stiffness, gene regulation, and DNA repair, here, we investigate the relationship between 3D genome structure and constricted migration in cancer cells. Using melanoma (A375) cells, we identify phenotypic differences in cells that have undergone multiple rounds of constricted migration. These cells display a stably higher migration efficiency, elongated morphology, and differences in the distribution of Lamin A/C and heterochromatin. Hi‐C experiments reveal differences in chromosome spatial compartmentalization specific to cells that have passed through constrictions and related alterations in expression of genes associated with migration and metastasis. Certain features of the 3D genome structure changes, such as a loss of B compartment interaction strength, are consistently observed after constricted migration in clonal populations of A375 cells and in MDA‐MB‐231 breast cancer cells. Our observations suggest that consistent types of chromosome structure changes are induced or selected by passage through constrictions and that these may epigenetically encode stable differences in gene expression and cellular migration phenotype.

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“…Extracellular physical forces can also affect nuclear mechanics and chromosome structure. Mechanical cues in a cell’s environment can lead to a spatial redistribution of chromatin (Heo et al , 2021). Irreversible stretching of chromatin domains has been observed in some nuclei aspirated into narrow micropipettes (Irianto et al , 2017b), and external cellular forces can even affect gene expression through direct chromatin deformations (Tajik et al , 2016).…”

Section: Introductionmentioning

confidence: 99%

Constricted migration is associated with stable 3D genome structure differences in cancer cell

Golloshi

Freeman

Das

et al. 2019

Preprint

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To spread from a localized tumor, metastatic cancer cells must squeeze through constrictions that cause major nuclear deformations. Since chromosome structure affects nucleus stiffness, gene regulation and DNA repair, here we investigate how confined migration affects or is affected by 3D genome structure. Using melanoma (A375) cells, we identify phenotypic differences in cells that have undergone 10 rounds of constricted migration. These cells display a stable increase in migration efficiency, elongated morphology, and an abnormal distribution of Lamin A/C and heterochromatin. Using Hi-C, we observe changes in chromosome spatial compartmentalization specific to constricted cells and related alterations in expression of genes associated with migration and metastasis. These cells also show increased nuclear deformations when cultured in a 3D collagen matrix and altered behavior when co-cultured with fibroblasts in organoids. Our observations reveal a relationship between chromosome structure changes, metastatic gene signatures, and the abnormal nuclear appearance of aggressive melanoma.

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Chemo-Mechanical Cues Modulate Nano-Scale Chromatin Organization in Healthy and Diseased Connective Tissue Cells

Cited by 7 publications

References 69 publications

How enzymatic activity is involved in chromatin organization

How enzymatic activity is involved in chromatin organization

Constricted migration is associated with stable 3D genome structure differences in cancer cells

Constricted migration is associated with stable 3D genome structure differences in cancer cell

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