# Dynamics of cardiac nuclei in heart disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $390,000

## Abstract

PROJECT SUMMARY/ABSTRACT
 Epigenetic processes have been implicated in control of cardiac development and in the incidence and
progression of disease. Heart failure in particular has been shown to involve the actions of chromatin remodeling
enzymes and to proceed by temporal reorganization of histone modifications and gene expression. The scientific
premise of this application is that understanding the principles of chromatin structure-function, including the roles
of specific molecular targets such as the linker histone H1 family, is key to re-engineering healthy transcriptomes
in the setting of disease. Based on preliminary data implicating its role in fibroblast phenotype, we will
mechanistically investigate the role of linker histone H1.0 in chromatin organization, using gain- and loss-of-
function approaches in cells and in vivo. We hypothesize that precise structural orientation of the genome is
underpinned by cell type-specific molecular processes and that disease results from reorganization of global
genome architecture, thereby enabling pathologic gene expression. To test this hypothesis, we will perform the
first ever reconstruction of genome topology on distinct cell types—fibroblasts and myocytes—from the same
organ. We will precisely measure differences in chromatin architecture in fibroblast nuclei from male and female
mice, examining the role of sex differences in genome organization as a potential unexplored contributor to
differences in gene expression and cardiovascular phenotype between the sexes. We will use dCas CLOuD9-
based chromatin loop reorganization tools to definitively test the causative role of chromatin interactions in
transcription and fibroblast activation. Based on preliminary data implicating a privileged role for linker histone
H1.0 in cardiac fibroblasts, we will examine the molecular mechanisms whereby H1.0 controls fibroblast gene
expression and locus specific chromatin accessibility. We will use gain- and loss-of-function approaches in
isolated fibroblasts to examine the role of histone H1.0 to regulate nuclear condensation, fibroblast gel
contraction, proliferation and myofibroblast protein expression. We will conclusively determine the in vivo role of
histone H1.0 in cardiac fibroblast phenotype under basal conditions and in the setting of pressure overload, beta
adrenergic stress by isoproterenol, or ischemic injury. This approach will allow us to test the role of histone H1.0
to regulate assembly of specific chromatin neighborhoods identified in our genome structure studies as well as
to examine whether these neighborhoods are reorganized in a histone H1.0-dependent manner in vivo
concomitant with development of disease. The proposed experiments will provide mechanistic insights into how
histone H1.0 contributes to fibroblast activation and cardiac function in vivo, revealing molecular details
underpinning epigenetic control of the heart’s response to injury.

## Key facts

- **NIH application ID:** 10878769
- **Project number:** 5R01HL105699-12
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Thomas M. Vondriska
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2011-01-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878769

## Citation

> US National Institutes of Health, RePORTER application 10878769, Dynamics of cardiac nuclei in heart disease (5R01HL105699-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10878769. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*