Role of epigenetics in liver-specific gene transcription, hepatocyte differentiation, and stem cell reprogrammation

Liver toxicity observed during (pre)clinical studies is often a major reason for stopping the development of promising drug candidates. Therefore, the pharmaceutical industry is strongly interested in establishing in vitro screening models to detect hepatotoxicity, and especially chronic liver toxicity, early in the drug development process. However, the currently available liver-based in vitro models suffer from phenotypic instability that cannot be fully overcome by introduction of cell-cell and cell-extracellular matrix contacts. New strategies must be developed. This paper reviews the possibilities of epigenetic modifiers, including inhibitors of histone deacetylases and DNA methyltransferases, (i) to generate metabolically competent long-term cultures of primary hepatocytes and (ii) to 'trans'differentiate adult stem cells into hepatocyte-like cells.