Single-cell multi-modal chromatin profiles revealing epigenetic regulations of cells in hepatocellular carcinoma

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Clinical and Translational Medicine Pub Date : 2024-08-29 DOI:10.1002/ctm2.70000

Chunqing Wang, Waidong Huang, Yu Zhong, Xuanxuan Zou, Shang Liu, Jie Li, Yunfan Sun, Kaiqian Zhou, Xi Chen, Zihao Li, Shanshan Wang, Yaling Huang, Yinqi Bai, Jianhua Yin, Xin Jin, Shiping Liu, Yue Yuan, Qiuting Deng, Miaomiao Jiang, Chuanyu Liu, Longqi Liu, Xun Xu, Liang Wu

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Abstract

Background

Various epigenetic regulations systematically govern gene expression in cells involving various biological processes. Dysregulation of the epigenome leads to aberrant transcriptional programs and subsequently results in diseases, such as cancer. Therefore, comprehensive profiling epigenomics is essential for exploring the mechanisms underlying gene expression regulation during development and disease.

Methods

In this study, we developed single-cell chromatin proteins and accessibility tagmentation (scCPA-Tag), a multi-modal single-cell epigenetic profile capturing technique based on barcoded Tn5 transposases and a droplet microfluidics platform. scCPA-Tag enables the simultaneous capture of DNA profiles of histone modification and chromatin accessibility in the same cell.

Results

By applying scCPA-Tag to K562 cells and a hepatocellular carcinoma (HCC) sample, we found that the silence of several chromatin-accessible genes can be attributed to lysine-27-trimethylation of the histone H3 tail (H3K27me3) modification. We characterized the epigenetic features of the tumour cells and different immune cell types in the HCC tumour tissue by scCPA-Tag. Besides, a tumour cell subtype (C2) with more aggressive features was identified and characterized by high chromatin accessibility and a lower abundance of H3K27me3 on tumour-promoting genes.

Conclusions

Our multi-modal scCPA-Tag provides a comprehensive approach for exploring the epigenetic landscapes of heterogeneous cell types and revealing the mechanisms of gene expression regulation during developmental and pathological processes at the single-cell level.

Highlights

scCPA-Tag offers a highly efficient and high throughput technique to simultaneously profile histone modification and chromatin accessibility within a single cell.
scCPA-Tag enables to uncover multiple epigenetic modification features of cellular compositions within tumor tissues.
scCPA-Tag facilitates the exploration of the epigenetic landscapes of heterogeneous cell types and provides the mechanisms governing gene expression regulation.

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揭示肝癌细胞表观遗传调控的单细胞多模式染色质图谱

背景各种表观遗传调控系统地控制着细胞中涉及各种生物过程的基因表达。表观基因组的失调会导致转录程序异常，进而引发癌症等疾病。因此，全面剖析表观基因组学对于探索发育和疾病过程中基因表达调控的机制至关重要。方法在这项研究中，我们开发了单细胞染色质蛋白和可及性标记技术（scCPA-Tag），这是一种基于条形码 Tn5 转座酶和液滴微流控平台的多模式单细胞表观遗传学图谱捕获技术。scCPA-Tag 可同时捕获同一细胞中组蛋白修饰和染色质可及性的 DNA 图谱。结果通过将 scCPA-Tag 应用于 K562 细胞和肝细胞癌（HCC）样本，我们发现几个染色质可及性基因的沉默可归因于组蛋白 H3 尾部的赖氨酸-27-三甲基化（H3K27me3）修饰。我们利用 scCPA-Tag 分析了 HCC 肿瘤组织中肿瘤细胞和不同免疫细胞类型的表观遗传学特征。此外，我们还发现了一种更具侵袭性特征的肿瘤细胞亚型（C2），其特点是染色质可及性高、促瘤基因上的 H3K27me3 丰度较低。结论我们的多模式 scCPA-Tag 为探索异质细胞类型的表观遗传景观提供了一种全面的方法，并在单细胞水平上揭示了发育和病理过程中基因表达的调控机制。亮点 scCPA-Tag 提供了一种高效率、高通量的技术，可同时分析单细胞内组蛋白修饰和染色质的可及性。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.