Chromatin Structural Gene Expression Stratifies Cardiac Cell Populations in Health and Disease
Author ORCID
Manuel Rosa-Garrido 0000-0002-2169-3972
Xiaoxiao Geng 0009-0009-9809-5266
Rujula Pradeep 0009-0000-2175-6024
Riley Porter 0009-0007-6734-7745
Lucía García-Gutiérrez 0000-0003-4396-4814
Min Xie 0000-0002-2967-3490
Adam Wende 0000-0002-5536-4675
Jianyi Zhang 0000-0002-3955-6554
Isidoro Cobo 0000-0002-2065-535X
Thanh Nguyen 0000-0002-8440-1594
Publication Date
9-2-2025
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 (snRNA-seq) 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 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.
Keywords
HMGN3, Cardiac Disease, Chromatin Structure
Repository
Zenodo
Distribution License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Access Instructions
This data is available under the CC-BY 4.0 License
Funder
Funder: National Institutes of Health
Funder DOI: 10.13039/100000002
P01HL160476
Funder: National Institutes of Health
Funder DOI: 10.13039/100000002
5R01HL131017-08
Funder: National Institutes of Health
Funder DOI: 10.13039/100000002
R01 HL167872
