Chromatin Structural Gene Expression Stratifies Cardiac Cell Populations in Health and Disease [Dataset]

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.染色质结构在调控基因表达、维持细胞身份中发挥核心作用，但目前对于驱动心脏疾病中此类过程的结构因子仍缺乏清晰认知。为探究此类结构因子能否区分健康与病变的心脏细胞群，研究团队通过全面的文献调研，构建了一套完整的染色质结构基因列表。将该列表应用于已发表的、针对伴或不伴扩张型心肌病（dilated cardiomyopathy, DCM）的人类心脏样本的单细胞核RNA测序（single-nuclei RNA sequencing, snRNA-seq）数据集后，研究团队发现，染色质结构基因的表达可依据疾病状态，有效实现心肌细胞与成纤维细胞群的分型。病变心肌细胞表现出收缩基因表达下调、心肌病标志物表达上调的特征，而成纤维细胞则呈现出激活特征增强的表型。在上述因子中，HMGN3成为重点关注的候选靶点：其在人类患者的心肌细胞、以及小鼠压力超负荷模型与猪心肌梗死模型的衰竭心肌细胞中，均呈现出持续的表达下调。在AC16细胞系中开展的功能实验显示，敲低HMGN3可促进细胞凋亡、诱导基因表达发生显著改变，并通过改变组蛋白H3K27ac的分布模式，重塑染色质结构。本研究结果确认HMGN3是病变心肌细胞中染色质架构的潜在调控因子，凸显了染色质结构变化在区分病理心脏状态中的应用价值，并进一步证实了染色质组织在塑造心脏表型中的关键作用。