Single-Cell Multiomic Analysis Revealed the Transcriptional and Epigenetic Regulatory Characteristics of Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma (ESCC) epigenomic or chromatin accessibility dysregulation drives aberrant transcriptional programs. This promotes ESCC proliferation and metastasis, which leads to poor prognosis in ESCC patients. Due to tumor heterogeneity, researches on chromatin accessibility at cell line or tissue level is difficult to reflect the true activation status of ESCC oncogenes accurately, as a result of which studies on ESCC chromatin accessibility at the single-cell level are urgently needed. In this study, scATAC-seq technology was firstly used to sequence 8 ESCC samples of all clinicopathological stages, and this was integrated with scRNA-seq, bulk RNA-seq and Hi-C data, and then chromatin accessibility and transcription landscape of ESCC tumors and their microenvironment (TME) throughout the whole cycle were generated in a multi-omics approach. Additionally, we identified characteristic epithelial cells molecules activated by regulatory elements at different clinical stages in ESCC, what's more, SERPINH1 could be considered as an early ESCC clinical marker. Moreover, the dynamic chromatin accessibility changes related to cell differentiation and immune escape in cancer associated fibroblasts (CAFs), tumor associated macrophages (TAMs) and T cells in ESCC TME were clarified. Furthermore, we revealed the chromatin regulation mechanism of cell communication between epithelial cells and TME. Above all, we used multiomics methods elucidate the epigenetic regulatory basis of ESCC heterogeneity and tumor microenvironment evolution, understanding the mechanism of oncogene activation in different stages of ESCC at the single-cell level, providing an important basis for the precision treatment of ESCC.Funding: This study is supported by the foundation of National Key Research and Development Program of China (Grant Number 2021YFC2401000), Natural Science Foundation of Shandong (ZR2021QC150, ZR2021QH142), National College Student Innovation and Entrepreneurship Training Program (202310439115).Declaration of Interest: The authors declare no competing interests.Ethical Approval: All these data were collected from the Cancer Hospital of Shandong First Medical University. In addition, the Ethics Committee of Shandong First Medical University approved this study. Written informed consent for sample collection and data analysis was obtained from all the patients.