Comprehensive analyses of partially methylated domains and differentially methylated regions in esophageal cancer reveal both cell-type- and cancer-specific epigenetic regulation

Genome Biology

Research

Yueyuan Zheng¹  Benjamin P. Berman²  H Phillip Koeffler³  De-Chen Lin⁴  Benjamin Ziman⁴  Uttam K. Sinha⁵  Allen S. Ho⁶  Li-Yan Xu⁷  En-Min Li⁷ 

[1] Clinical Big Data Research Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, People’s Republic of China;Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, USA;Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel;Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, USA;Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, USA;Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, and Norris Comprehensive Cancer Center, University of Southern California, 2250 Alcazar Street – CSA 207D, 90033, Los Angeles, CA, USA;Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, USA;Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA;The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Guangdong, China;

关键词: Esophageal cancer;    Partially methylated domains;    DMRs;    Cell-type specificity;   

DOI  :  10.1186/s13059-023-03035-3

 received in 2023-01-13, accepted in 2023-08-10,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundAs one of the most common malignancies, esophageal cancer has two subtypes, squamous cell carcinoma and adenocarcinoma, arising from distinct cells-of-origin. Distinguishing cell-type-specific molecular features from cancer-specific characteristics is challenging.ResultsWe analyze whole-genome bisulfite sequencing data on 45 esophageal tumor and nonmalignant samples from both subtypes. We develop a novel sequence-aware method to identify large partially methylated domains (PMDs), revealing profound heterogeneity at both methylation level and genomic distribution of PMDs across tumor samples. We identify subtype-specific PMDs that are associated with repressive transcription, chromatin B compartments and high somatic mutation rate. While genomic locations of these PMDs are pre-established in normal cells, the degree of loss is significantly higher in tumors. We find that cell-type-specific deposition of H3K36me2 may underlie genomic distribution of PMDs. At a smaller genomic scale, both cell-type- and cancer-specific differentially methylated regions (DMRs) are identified for each subtype. Using binding motif analysis within these DMRs, we show that a cell-type-specific transcription factor HNF4A maintains the binding sites that it generates in normal cells, while establishing new binding sites cooperatively with novel partners such as FOSL1 in esophageal adenocarcinoma. Finally, leveraging pan-tissue single-cell and pan-cancer epigenomic datasets, we demonstrate that a substantial fraction of cell-type-specific PMDs and DMRs identified here in esophageal cancer are actually markers that co-occur in other cancers originating from related cell types.ConclusionsThese findings advance our understanding of DNA methylation dynamics at various genomic scales in normal and malignant states, providing novel mechanistic insights into cell-type- and cancer-specific epigenetic regulations.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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