# Folding, Misfolding, and Unfolding: How human 3D genome structure resists, adapts, or succumbs to physical stresses in health and disease

> **NIH NIH R35** · UNIVERSITY OF TENNESSEE KNOXVILLE · 2024 · $405,865

## Abstract

Project Summary/Abstract:
The 3D folding of human chromosomes inside the nucleus affects critical biological processes, including gene
regulation and DNA repair, while also influencing the physical properties of the nucleus. To make progress
toward our overarching goal of understanding the principles of chromosome folding and their importance in
health and disease, my research program investigates the responses of 3D genome structure to physical
perturbations. We examine alterations of chromosome structure in the context of DNA damage, nucleus
structure disruption by lamin mutation, cell migration through narrow constrictions, and externally applied
forces. Our recent work has revealed a striking robustness of chromosome structure to many transient
perturbations, but has shown stable alterations in the 3D genome and cell phenotype can result from chronic or
repeated stresses. By comparing complementary systems, we have identified different levels of the
chromosome structure hierarchy that respond to different stresses: DNA damage results in strengthening of
the local loop and topologically associating domain (TAD) structure while physical deformations of the nucleus
associated with altered spatial segregation of heterochromatin and euchromatin. New research in a variety of
systems is revealing the important role of nucleus mechanosensation in cell fate decisions. We are now well-
positioned to connect cellular and imaging observations of such phenomena with the 3D genome changes that
accompany them. In this next funding period, our research will examine what molecular mechanisms contribute
to stable 3D genome and phenotype changes after cancer cells pass through multiple rounds of constricted
migration. We will contrast this constricted migration system with responses elicited by externally applied
forces on the cell. We will examine how disruption of nucleus architecture by a lamin mutation affects genome
structure reprogramming during differentiation and contributes to the patient phenotypes of the premature
aging disease Progeria. As many of these stressors also induce DNA damage, we will finally investigate the
effects of chromosome structure alterations after DNA damage on DNA repair, gene regulation, and cellular
response to subsequent stresses. Observations across our experimental systems combined with
computational analysis and modeling will clarify the relationship between changes in chromosome structure
and gene expression and reveal how microscopically observed alterations in chromosome conformation relate
to changes in contact patterns detected by chromosome conformation capture (Hi-C) family techniques. Our
previous innovations in single cell genomic data analysis and integration position us to investigate how
average shifts in cell population behavior connect to the heterogeneity and dynamics of chromosome structure
and gene expression at a single cell level. Defining connections between physical perturbations, genome
architecture, ...

## Key facts

- **NIH application ID:** 10842538
- **Project number:** 2R35GM133557-06
- **Recipient organization:** UNIVERSITY OF TENNESSEE KNOXVILLE
- **Principal Investigator:** Rachel Patton McCord
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $405,865
- **Award type:** 2
- **Project period:** 2019-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842538

## Citation

> US National Institutes of Health, RePORTER application 10842538, Folding, Misfolding, and Unfolding: How human 3D genome structure resists, adapts, or succumbs to physical stresses in health and disease (2R35GM133557-06). Retrieved via AI Analytics 2026-06-25 from https://api.ai-analytics.org/grant/nih/10842538. Licensed CC0.

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