Transient Partial Inhibition of DNA Polymerase α Promotes Chromatin Plasticity and Enhances Human Cell Reprogramming

Low-dose, transient inhibition of the lagging-strand DNA polymerase complex catalytic subunit PolA1 markedly enhances reprogramming of human PBMCs into iPSCs.

• Why it matters: Somatic reprogramming needs extensive epigenomic remodeling, but how replication-linked chromatin plasticity is regulated during cell-fate conversion is not well understood.
• What they did: PBMCs were reprogrammed with fine-tuned PolA1 inhibition, followed by integrated imaging and single-nucleus multiomic analyses to track early chromatin accessibility and replication-coupled histone incorporation.
• The result: PolA1-inhibited cells show increased chromatin accessibility after factor delivery, improved survival and resilience under reprogramming stress, preserved genomic stability, and accelerated acquisition of pluripotent features with enhanced differentiation potential.