Human DCM-time machine unravels cell state changes during primitive gut tube differentiation

Cell state changes in development and differentiation are directed by gene and enhancer activity dynamics, which are difficult to study in real time. We introduce the DCM-time machine into human induced pluripotent stem cells to enable retrospective, genome-wide tracing of transcriptional activity. This system labels active genes and enhancers with DCM methylation marks that are propagated during S-phase. Applied to differentiation of induced pluripotent stem cells towards definitive endoderm and primitive gut tube, the DCM-time machine resolves activity dynamics and enables integration with transcription factor networks and CpG methylation profiles. Together, the human DCM-time machine provides a powerful platform for dissecting both healthy and pathogenic embryogenesis.