食管癌作为最常见的恶性肿瘤之一，分为鳞状细胞癌和腺癌两个亚型，源自不同的起源细胞。将细胞类型特异性分子特征与癌症特异性特征区分开是具有挑战性的。我们对来自两个亚型的45个食管肿瘤和非恶性样本进行了全基因组亚硫酸盐测序数据的分析。我们开发了一种新颖的序列感知方法来识别大片部分甲基化域（PMDs），揭示了肿瘤样本中PMDs的甲基化水平和基因组分布的深刻异质性。我们确定了与亚型特异性PMDs相关联的转录抑制、染色质B亚区和高体细胞突变率。尽管这些PMDs在正常细胞中的基因组位置是已建立的，但在肿瘤中丢失的程度显著更高。我们发现，H3K36me2的细胞类型特异性沉积可能是PMDs基因组分布的基础。在较小的基因组尺度上，为每个亚型确定了细胞类型特异性和癌症特异性的差异甲基化区域（DMRs）。通过在这些DMRs中进行结合基序分析，我们展示了细胞类型特异性转录因子HNF4A在正常细胞中保持其产生的结合位点，同时在食管腺癌中与新伙伴（如FOSL1）协同建立新的结合位点。最后，利用全组织单细胞和全癌症表观基因组数据集，我们证明在食管癌中鉴定出的细胞类型特异性PMDs和DMRs的实际上是与相关细胞类型起源的其他癌症共同存在的标记。这些发现推进了我们对正常和恶性状态下DNA甲基化动态的理解，为细胞类型和癌症特异性表观遗传调控提供了新的机制洞察。 © 2023. BioMed Central Ltd., 包括 Springer Nature 的一部分。

As 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.We 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.These 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.© 2023. BioMed Central Ltd., part of Springer Nature.