Project description:Human induced pluripotent stem cells (hiPSCs) are useful as a tool for reproducing neural development in vitro. However, each hiPSC line has a different ability to differentiate into specific lineages, as known as differentiation propensity, resulting in reduced reproducibility and increased time and cost requirements for research use. To overcome this issue, we searched for predictive signatures of neural differentiation propensity of hiPSCs using DNA methylation which is the main modulator of cellular properties. We obtained 32 lines of hiPSC and its comprehensive DNA methylation data by Infinium MethylationEPIC beadchip. To assess the neural differentiation efficiency of these hiPSCs, we measured the percentage of PAX6-positive cells on day 7 of neural stem cell induction by the dual-SMAD inhibition protocol. Using DNA methylation data of undifferentiated hiPSCs and their measured differentiation efficiency into neural stem cells as the set of data, and HSIC Lasso, a machine learning-based nonlinear feature selection method, we attemted to identify neural differentiation associated differentially methylated sites. Epigenome-wide unsupervised clustering could not distinguish between hiPSCs with varying differentiation efficiency. On the other hand, HSIC Lasso identified 62 probes that can explain the neural differentiation efficiency of hiPSCs. Selected features by HSIC Lasso were particularly enriched within the 3 Mbp on chromosome 5, harboring the IRX2, C5orf38, and IRX1 genes. Within this region, DNA methylation rates were correlated with neural differentiation efficiency particular to female hiPSCs and negatively correlated with gene expression of the IRX1/2 genes. In addition, forced expression of the IRX1/2 genes impaired the neural differentiation ability of hiPSCs. We have shown for the first time that DNA methylation state on the IRX1/2 genes of hiPSCs is predictive biomarker of their ability for neural differentiation. The predictive markers for neural differentiation efficiency identified in this study can be useful for selection of suitable undifferetiated hiPSCs prior to differentiation induction.

Dataset Information

Variation of DNA methylation on the IRX1/2 genes is responsible for the neural differentiation propensity in human induced pluripotent stem cells [Illumina Infunium MethylationEPIC]

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