Alladi Ramakrishnan Hall

How do forces transmitted from a cell's environment affect DNA organization?

Vivek Shenoy

University of Pennsylvania

Microscale changes in tissue environment are translated to changes in cell behavior and phenotype, yet the mechanisms behind how these phenotypic changes occur are poorly understood. Here, we describe and model chromatin, which stores genetic information within the cell nucleus, as a dynamic nanomaterial whose configuration is modulated by chemo-mechanical cues in the microenvironment [1]. Our findings indicate that physiologic chemo-mechanical cues can directly regulate chromatin architecture in progenitor cell populations. Through direct experimental observation and modeling that incorporates phase transitions and histone methylation kinetics, we demonstrate that soft environmental cues drive chromatin relocalization to the nuclear boundary (leading to the formation of Lamin-Associated Domains) and compaction. Conversely, dynamic stiffening attenuates these changes. We show how methylation and acetylation impact the spatial distribution of the stiffness of the nucleus. Interestingly, in diseased human fibrous tissue cells, this link between mechanical inputs and chromatin nano-scale remodeling is abrogated [2]. These data indicate that chromatin dynamics and plasticity may be hallmarks of disease progression and targets for therapeutic intervention.

1] S. Heo et al., Aberrant Chromatin Reorganization in Cells from Diseased Fibrous Connective Tissue in Response to Altered Chemo-mechanical Cues NATURE BIOMEDICAL ENGINEERING, s41551-022-00910-5, 1-15, 2023
[2] F. Alisafaei, D. S. Jokhun, G. V. Shivashankar, V. B. Shenoy Regulation of Nuclear Architecture, Mechanics and Nucleo-cytoplasmic Shuttling of Epigenetic Factors by Cell Geometric Constraints PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, 116(27): 13200-13209, 2020