A Nondimensional Model Reveals Alterations in Nuclear Mechanics upon Hepatitis C Virus Replication

Morphology of the nucleus is an important regulator of gene expression. Nuclear morphology is in turn a function of the forces acting on it and the mechanical properties of the nuclear envelope. Here, we present a two-parameter, nondimensional mechanical model of the nucleus that reveals a relations...

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Bibliographic Details
Published in:Biophysical journal 2019-04, Vol.116 (7), p.1328-1339
Main Authors: Balakrishnan, Sreenath, Mathad, Suma S., Sharma, Geetika, Raju, Shilpa R., Reddy, Uma B., Das, Saumitra, Ananthasuresh, G.K.
Format: Article
Language:English
Subjects:
Actins - chemistry
Actins - metabolism
Cell Line, Tumor
Elastic Modulus
Hepacivirus - physiology
Hepatocytes - metabolism
Hepatocytes - virology
Humans
Lamin Type A - chemistry
Lamin Type A - metabolism
Models, Theoretical
Nuclear Envelope - chemistry
Nuclear Envelope - virology
Virus Replication
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Summary:Morphology of the nucleus is an important regulator of gene expression. Nuclear morphology is in turn a function of the forces acting on it and the mechanical properties of the nuclear envelope. Here, we present a two-parameter, nondimensional mechanical model of the nucleus that reveals a relationship among nuclear shape parameters, such as projected area, surface area, and volume. Our model fits the morphology of individual nuclei and predicts the ratio between forces and modulus in each nucleus. We analyzed the changes in nuclear morphology of liver cells due to hepatitis C virus (HCV) infection using this model. The model predicted a decrease in the elastic modulus of the nuclear envelope and an increase in the pre-tension in cortical actin as the causes for the change in nuclear morphology. These predictions were validated biomechanically by showing that liver cells expressing HCV proteins possessed enhanced cellular stiffness and reduced nuclear stiffness. Concomitantly, cells expressing HCV proteins showed downregulation of lamin-A,C and upregulation of β-actin, corroborating the predictions of the model. Our modeling assumptions are broadly applicable to adherent, monolayer cell cultures, making the model amenable to investigate changes in nuclear mechanics due to other stimuli by merely measuring nuclear morphology. Toward this, we present two techniques, graphical and numerical, to use our model for predicting physical changes in the nucleus.
ISSN:0006-3495
1542-0086
DOI:10.1016/j.bpj.2019.02.013