TET1 potentiates human iPS cell reprogramming by rectifying extraembryonic gene noises

Abstract

SUMMARYInduced pluripotent stem cells (iPSCs) exhibit inconsistent differentiation potential, negatively impacting their downstream applications. Here, we potentiated their reprogramming by adding ten-eleven translocation 1 (TET1), a DNA demethylase, to produce TET1-iPSCs (T-iPSCs). By comparing the differentiation efficiencies of 46 in-house-generated iPSC clones, we identified an extraembryonic gene signature linked to differentiation defects. The extraembryonic signature was upregulated when all three TET genes were knocked out in human embryonic stem cells. T-iPSCs with enhanced epithelialized morphology, a trait attributable to TET1 activity during reprogramming, exhibited uniform TET1 expression and lacked the identified extraembryonic signature. These T-iPSCs differentiated into ventral midbrain dopaminergic neurons with unprecedented fidelity and efficiency. Our data collectively revealed a deviation from the genuine embryonic gene profile in conventional human iPSCs, which was amendable by including TET1 in the reprogramming cocktail. We recommend the proposed T-iPSC production pipeline as a de facto standard for human iPSC reprogramming.