# Chromatin structural gene expression stratifies cardiac cell populations in health and disease

## TL;DR

This study shows that chromatin structure changes in heart cells can distinguish healthy from diseased states and identifies HMGN3 as a key player in heart disease.

## Contribution

The study introduces a novel approach using chromatin structural gene expression to classify cardiac cell populations in health and disease.

## Key findings

- Chromatin structural gene expression effectively stratifies cardiomyocyte and fibroblast populations by disease status.
- HMGN3 is consistently downregulated in DCM patients and heart failure models, and its depletion alters chromatin structure and gene expression.
- HMGN3 depletion in AC16 cells promotes apoptosis and changes chromatin architecture marked by H3K27ac distribution.

## Abstract

Chromatin structure plays a central role in regulating gene expression and maintaining cellular identity, yet the structural factors driving these processes in cardiac disease remain poorly defined. To investigate whether these factors can distinguish healthy from diseased cardiac cell populations, we generated a comprehensive list of chromatin structural genes based on an extensive literature review. Applying this list to a published single-nuclei RNA sequencing dataset from human hearts with and without dilated cardiomyopathy (DCM), we found that chromatin structural gene expression effectively stratified cardiomyocyte and fibroblast populations by disease status. Diseased cardiomyocytes exhibited reduced expression of contractile genes and increased expression of cardiomyopathy markers, while fibroblasts showed enhanced activation signatures. Among these factors, HMGN3 emerged as a candidate of interest, showing consistent downregulation in cardiomyocytes from DCM human patients, as well as in mouse (pressure overload) and pig (myocardial infarction) models of heart failure. Functional studies in AC16 cells revealed that HMGN3 depletion promoted apoptosis, induced significant changes in gene expression, and reorganized chromatin structure by altering the distribution of the H3K27ac histone mark. These findings identify HMGN3 as a potential regulator of chromatin architecture in diseased cardiomyocytes, highlight the utility of chromatin structural changes in distinguishing pathological cardiac states, and reinforce the role of chromatin organization in shaping the cardiac phenotype.