Identification of a specific reprogramming-associated epigenetic signature in human induced pluripotent stem cells

TLDR

Generation of hiPSCs requires successful epigenetic reprogramming, yet despite similar epigenomes to hESCs, hiPSCs retain somatic‑origin marks and aberrant methylation patterns. The study aims to determine whether varying somatic cell sources and reprogramming efficiencies affect epigenetic aberrations in hiPSCs. The authors assessed epigenomic integrity across 17 hiPSC lines from six cell types with differing reprogramming efficiencies. Epigenetic aberrations are a universal feature of hiPSCs, independent of cell source, with higher reprogramming efficiency linked to fewer methylation changes; shared and line‑specific aberrations affect gene expression, and a nine‑gene reprogramming‑specific signature distinguishes hiPSCs from hESCs across all sources and states.

Abstract

Generation of human induced pluripotent stem cells (hiPSCs) by the expression of specific transcription factors depends on successful epigenetic reprogramming to a pluripotent state. Although hiPSCs and human embryonic stem cells (hESCs) display a similar epigenome, recent reports demonstrated the persistence of specific epigenetic marks from the somatic cell type of origin and aberrant methylation patterns in hiPSCs. However, it remains unknown whether the use of different somatic cell sources, encompassing variable levels of selection pressure during reprogramming, influences the level of epigenetic aberrations in hiPSCs. In this work, we characterized the epigenomic integrity of 17 hiPSC lines derived from six different cell types with varied reprogramming efficiencies. We demonstrate that epigenetic aberrations are a general feature of the hiPSC state and are independent of the somatic cell source. Interestingly, we observe that the reprogramming efficiency of somatic cell lines inversely correlates with the amount of methylation change needed to acquire pluripotency. Additionally, we determine that both shared and line-specific epigenetic aberrations in hiPSCs can directly translate into changes in gene expression in both the pluripotent and differentiated states. Significantly, our analysis of different hiPSC lines from multiple cell types of origin allow us to identify a reprogramming-specific epigenetic signature comprised of nine aberrantly methylated genes that is able to segregate hESC and hiPSC lines regardless of the somatic cell source or differentiation state.