# Dynamics of Cardiac Nuclei in Heart Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $390,000

## Abstract

PROJECT SUMMARY/ABSTRACT
 While the sequence of the genome is invariant across cell types, its function varies widely. As a result,
the epigenome, which is composed of histone variants, DNA modification, chromatin structural proteins, and the
cadre of proteins that add, remove and interpret post-translational modifications, is of principle importance to
understanding the function of cardiac and other cell types. A critical question with basic and translational impact
in cardiac physiology is: how does the cell maintain the correct chromatin environment conducive to a healthy
adult myocyte transcriptome?
 In preliminary studies for this renewal, we have adapted methods for chromatin conformation analysis to
work in adult cardiac myocytes. We have mapped topologically associating domains (TADs) in myocytes from
the basal and pressure overloaded heart, identifying regions of chromatin accessibility and partitioning of genes
into active and inactive compartments based on topology. RNA-seq studies have been carried out in these same
models to understand the impact on transcription. Mechanistically, we have revealed the actions of chromatin
structural proteins in epigenomic specification, which, together with our global measurements of chromatin
accessibility and gene expression, serve as the scientific premise for this grant. In addition, we have developed
the techniques to determine, with individual locus specificity, how these proteins (including the high mobility
group members HMGB2, HMGA1 and HMGN5, plus Nap1 and others identified by proteomics) control local
accessibility and transcription through the interaction with other histone marks.
 We hypothesize that chromatin structure serves as a principal integrator of environmental stress
and the other major determinant of all common disease: population scale genetic variability. We propose
three aims to test this hypothesis: first, we will determine the fundamental structure-function relationship of
the cardiac epigenome in the healthy and diseased heart using Hi-C and RNA-seq. Second, we will determine
the logic for transcriptional regulation by chromatin structural proteins at individual loci using a combination of
targeted chromatin accessibility analysis, proteomics, ChIP-seq and gain/loss of function. Third, we will identify
and validate functional motifs within the epigenome, revealing how genetic variation combines with differential
protein binding to specify altered transcription, and thus cardiac phenotype, across a population.

## Key facts

- **NIH application ID:** 9924638
- **Project number:** 5R01HL105699-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Thomas M. Vondriska
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2011-01-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9924638

## Citation

> US National Institutes of Health, RePORTER application 9924638, Dynamics of Cardiac Nuclei in Heart Disease (5R01HL105699-09). Retrieved via AI Analytics 2026-06-23 from https://api.ai-analytics.org/grant/nih/9924638. Licensed CC0.

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