Epigenetic memory of environmental exposures as a mediator of liver disease.

Epigenetic changes are a common feature of human disease including liver disease and its progression to liver cancer. The most frequent form of liver cancer, hepatocellular carcinoma (HCC), is unusual because most of its causes, or etiologic drivers, are known and are dominated by environmental exposures including viral infection, alcohol abuse, and over-nutrition/metabolic syndrome. The epigenome is a regulatory system overlayed on the genetic material that regulates, when, where, and to what extent genes are expressed in developmental, cell-type, and disease-associated contexts. Deregulation of the epigenome has emerged as a major player in the pathologic effects of liver disease driving exposures, particularly during their early phases when genetic changes are uncommon. While it is inherent in the definition of an epigenetic process to be reversible, emerging evidence indicates that epigenetic changes persist after removal of the exposure and contribute to long-term risk of disease progression. In other systems, environmental exposures lead to beneficial adaptive changes in expression that facilitate processes such as wound healing, and these too are driven by epigenetic changes. What remains unclear, however, is what drives the transition from a beneficial epigenetic memory to a maladaptive scar, the epigenetic processes involved in forming these memories, and whether this process can be modulated for therapeutic purposes. In this review, we discuss these concepts in relation to liver disease and more broadly using examples from other tissue types and diseases, and finally consider how epigenetic therapies could be employed to reprogram maladaptive epigenetic memories to delay and/or prevent hepatocarcinogenesis.