# Analyzing the role of chromatin compaction in nuclear mechanics, structure, and function

> **NIH NIH R00** · UNIVERSITY OF MASSACHUSETTS AMHERST · 2020 · $249,000

## Abstract

The nucleus is the organelle which must properly transduce or resist biophysical forces to dictate the
spatial organization of the genome and to control mechanotransduction, factors which determine the
expression profile of the cell. The two major contributors to nuclear mechanics are lamins, intermediate
filaments lining the inner nuclear envelope, and chromatin, which fills the nucleus. Alteration of lamins and
chromatin compaction occur in many major human diseases and during healthy cell differentiation. In both
cases nuclear, cell, and tissue mechanics and morphology can change drastically. Currently, the
mechanistic basis for both disease-based nuclear blebs and healthy differentiation-based changes in
nuclear morphology and mechanics is unknown. My studies found that chromatin and its histone-mediated
compaction state and cross-linking dictated initial force response (< 30% strain) and morphology while also
contributing as a secondary factor to the lamin A dictated strain stiffening at longer deformations. I first
propose to use my developed microdissection, micromanipulation, and nanonewton-level force
measurement approach to further elucidate the role of nuclear mechanics in genome organization. During
nuclear stretching experiments I will determine how the chromatin responds to nuclear deformation through
imaging single chromosome loci (CRISPR labeling) and overall chromatin nano-structure. Second, I will
investigate the functional impact of the disease-relevant phenotype of nuclear blebbing and rupture that
can be caused or suppressed by chromatin-based nuclear mechanics. I will determine if nuclear blebs are
a symptom or a cause of disease, via live cell imaging and biochemical techniques to assay for systemic
DNA damage, proper transcription, and faithful segregation of genomic content in the bleb. Finally, I will
use the well-established primary cell model of keratinocytes to investigate the basis of nuclear morphology
changes during differentiation, progenitor to terminal, and loss of homeostasis upon Ras activation to mimic
cancer transition. Overall, I aim to develop an independent career investigating the mechanical basis of
morphology changes observed for more than 70 years in both disease and in healthy cell differentiation.

## Key facts

- **NIH application ID:** 10156090
- **Project number:** 4R00GM123195-03
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS AMHERST
- **Principal Investigator:** Andrew Daniel Stephens
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2020-08-06 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10156090

## Citation

> US National Institutes of Health, RePORTER application 10156090, Analyzing the role of chromatin compaction in nuclear mechanics, structure, and function (4R00GM123195-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10156090. Licensed CC0.

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