Looking at induced pluripotent stem cell (iPSC) differentiation through the lens of the noncoding genome

Clinical application of induced pluripotent stem cell–based (iPSC-based) therapies has recently experienced some success for the treatment of degenerative diseases; however, the long-term effects remain unknown. Comprehensive and cell type–specific validation of iPSC-derived cells is a crucial component of their clinical application. Incomplete analyses could obscure potentially dangerous downstream effects when used in a clinical setting. Recently, more comprehensive analyses of iPSC-derived cell types have revealed the retention of an epigenetic memory derived from the somatic cell type source used for pluripotential reprogramming. An epigenetic memory has the potential to be propagated throughout the differentiation process, leading to target cells harboring epigenetic vestiges of their parent somatic cell source. Retention of an epigenetic memory is characterized by aberrant gene expression in iPSCs relative to their native undifferentiated counterparts. Likely contributors to maintenance of epigenetic memory are long noncoding RNAs (lncRNAs) via their role in the regulation of epigenetic and epitranscriptomic modifications, in addition to being epigenetically and epitranscriptomically modified themselves. As epigenetic regulators, lncRNAs have recently been implicated in the regulation of stem cell differentiation and pluripotency programs. Considering the role of the noncoding genome in iPSC reprogramming and differentiation offers the potential to improve clinical outcomes of iPSC-derived tissues. This review will examine iPSC reprogramming, differentiation, target cell type validation, and maintenance of an epigenetic memory. The role of lncRNAs in regulating tissue-specific expression in the context of stem cell differentiation and pluripotency programs will also be reviewed. Exploration of the noncoding genome toward improving current validation standards and iPSC-associated clinical outcomes will be addressed in the future trends and directions.