Abstract
Determining cell identity and maturation status of differentiated pluripotent stem cells (PSCs) requires knowledge of the transcriptional and epigenetic trajectory of organs during development. Here, we generate a transcriptional and DNA methylation atlas covering 21 organs during human fetal development. Analysis of multiple isogenic organ sets shows that organ-specific DNA methylation patterns are highly dynamic between week 9 (W9) and W22 of gestation. We investigate the impact of reprogramming on organ-specific DNA methylation by generating human induced pluripotent stem cell (hiPSC) lines from six isogenic organs. All isogenic hiPSCs acquire DNA methylation patterns comparable to existing hPSCs. However, hiPSCs derived from fetal brain retain brain-specific DNA methylation marks that seem sufficient to confer higher propensity to differentiate to neural derivatives. This systematic analysis of human fetal organs during development and associated isogenic hiPSC lines provides insights in the role of DNA methylation in lineage commitment and epigenetic reprogramming in humans.
Highlights
Determining cell identity and maturation status of differentiated pluripotent stem cells (PSCs) requires knowledge of the transcriptional and epigenetic trajectory of organs during development
Setting the correct patterns of DNA methylation is crucial during development, but removing those during the reverse process of reprogramming somatic cells from any human tissue to pluripotency as induced pluripotent stem cells[13, 14] is important
After quality control (Supplementary Fig. 1), we applied multidimensional scaling (MDS) to the 111 NGS datasets and found that the four directions towards the corners of the MDS plot corresponded to the germ layers (Fig. 1b and Supplementary Fig. 2a)
Summary
Determining cell identity and maturation status of differentiated pluripotent stem cells (PSCs) requires knowledge of the transcriptional and epigenetic trajectory of organs during development. All isogenic hiPSCs acquire DNA methylation patterns comparable to existing hPSCs. hiPSCs derived from fetal brain retain brain-specific DNA methylation marks that seem sufficient to confer higher propensity to differentiate to neural derivatives. HiPSCs derived from fetal brain retain brain-specific DNA methylation marks that seem sufficient to confer higher propensity to differentiate to neural derivatives This systematic analysis of human fetal organs during development and associated isogenic hiPSC lines provides insights in the role of DNA methylation in lineage commitment and epigenetic reprogramming in humans. The gene expression signatures of iPSCs and ESCs are similar, when large numbers of lines are compared, individual lines are not necessarily identical[17,18,19,20] This led to the hypothesis that residual epigenetic memory may be retained from the tissue of origin. The DNA methylation pattern observed at W22 in some organs appears at least in part to be maintained during adulthood[32,33,34,35], suggesting lineage commitment
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