Epigenetic contributions, known to be important in AUD, pose another major challenge to utilizing hiPSC models. Incomplete tissue-specific erasure and aberrant de novo methylation during reprogramming somatic cells have effects on conversion efficiency and gene expression (Kim et al., 2010, 2011; Lister et al., 2011; Nazor et al., 2012; Oni and Hart, 2016). Epigenetic reset during conversion of somatic cells to a pluripotent state, even with residual methylation signatures, erases age-related marks (Lapasset et al., 2011) and may have an impact on other epigenetic marks contributing to AUD phenotype. One work-around for this could be to directly induce neurons from fibroblasts, which retain age-related epigenetic marks (Mertens et al., 2015a). In AUD, alcohol metabolism has a profound effect on epigenetic markers (Boschen et al., 2018; Krishnan et al., 2014; Zakhari, 2013), which may vary between CNS and peripheral cells, and careful consideration of reprogramming methods and epigenetic marks is essential for adequate disease modeling.
