Dppa2/4 Facilitate Epigenetic Remodeling during Reprogramming to Pluripotency

Highlights

• Depletion of Dppa2 and Dppa4 reduced reprogramming efficiency

• Overexpression of Dppa2 and Dppa4 improved reprogramming efficiency and kinetics

• Dppa2/4 overexpression induced ɣH2AX and chromatin decompaction via Parp1

• Depletion of Parp1 or H2AX abolished the effect of Dppa2/4 on chromatin remodeling

Summary

As somatic cells are converted into induced pluripotent stem cells (iPSCs), their chromatin is remodeled to a pluripotent configuration with unique euchromatin-to-heterochromatin ratios, DNA methylation patterns, and enhancer and promoter status. The molecular machinery underlying this process is largely unknown. Here, we show that embryonic stem cell (ESC)-specific factors Dppa2 and Dppa4 play a key role in resetting the epigenome to a pluripotent state. They are induced in reprogramming intermediates, function as a heterodimer, and are required for efficient reprogramming of mouse and human cells. When co-expressed with Oct4, Klf4, Sox2, and Myc (OKSM) factors, Dppa2/4 yield reprogramming efficiencies that exceed 80% and accelerate reprogramming kinetics, generating iPSCs in 2 to 4 days. When bound to chromatin, Dppa2/4 initiate global chromatin decompaction via the DNA damage response pathway and contribute to downregulation of somatic genes and activation of ESC enhancers, all of which enables an efficient transition to pluripotency. Our work provides critical insights into how the epigenome is remodeled during acquisition of pluripotency.