■: Disruption of the epigenome is a hallmark of human disease including liver cirrhosis and hepatocellular carcinoma (HCC). While genetic heterogeneity is an established effector of pathologic phenotypes, epigenetic heterogeneity is less well understood. Environmental exposures alter the liver-specific DNA methylation landscape and influence the onset of liver cancer. Given that currently available treatments are unable to target frequently mutated genes in HCC, there is an unmet need for novel therapeutics to prevent or reverse liver damage leading to hepatic tumorigenesis, which the epigenome may provide. We performed genome-wide profiling of DNA methylation, copy number, and gene expression from multiple liver regions from 31 patients with liver disease to examine their crosstalk and define the individual and combinatorial contribution of these processes to liver disease progression. We identify epigenetic heterogeneity hotspots that are conserved across patients. Elevated epigenetic heterogeneity associates with increased gene expression heterogeneity. Cirrhotic regions comprise two distinct cohorts, one exclusively epigenetic, and a second where epigenetic and copy number variations collaborate. Epigenetic heterogeneity hotspots are enriched for genes central to liver function (e.g., HNF1A) and known tumor suppressors (e.g., RASSF1A). These hotspots encompass genes including ACSL1, ACSL5, MAT1A, and ELFN1, which have phenotypic effects in functional screens, supporting their relevance to hepatocarcinogenesis. Moreover, epigenetic heterogeneity hotspots are linked to clinical measures of outcome. Conclusion: Substantial epigenetic heterogeneity arises early in liver disease development, targeting key pathways in the progression and initiation of both cirrhosis and HCC. Integration of epigenetic and transcriptional heterogeneity unveils putative epigenetic regulators of hepatocarcinogenesis.

中文翻译：

---

人类肝脏疾病进展中的表观遗传异质性热点


■：表观基因组的破坏是包括肝硬化和肝细胞癌(HCC)在内的人类疾病的标志。虽然遗传异质性是病理表型的既定效应因素，但表观遗传异质性却鲜为人知。环境暴露会改变肝脏特异性 DNA 甲基化景观并影响肝癌的发病。鉴于目前可用的治疗方法无法针对 HCC 中频繁突变的基因，因此对新疗法的需求尚未得到满足，以预防或逆转导致肝肿瘤发生的肝损伤，而表观基因组可能提供这种治疗方法。我们对 31 名肝病患者多个肝脏区域的 DNA 甲基化、拷贝数和基因表达进行了全基因组分析，以检查它们的串扰并确定这些过程对肝病进展的个体和组合贡献。我们确定了在患者中保守的表观遗传异质性热点。表观遗传异质性升高与基因表达异质性增加相关。肝硬化区域包括两个不同的群体，一个完全是表观遗传的，另一个是表观遗传和拷贝数变异共同作用的。表观遗传异质性热点富含肝功能核心基因（例如 HNF1A）和已知的肿瘤抑制基因（例如 RASSF1A）。这些热点包含 ACSL1、ACSL5、MAT1A 和 ELFN1 等基因，这些基因在功能筛选中具有表型效应，支持它们与肝癌发生的相关性。此外，表观遗传异质性热点与临床结果测量相关。 结论：显着的表观遗传异质性出现在肝病发展的早期，针对肝硬化和 HCC 进展和起始的关键途径。表观遗传和转录异质性的整合揭示了肝癌发生的假定表观遗传调节因子。