Chromatin-associated factors Dppa2 and Dppa4 guide epigenetic remodeling during reprogramming to pluripotency (RNA-seq)

As somatic cells are converted to iPSCs, their chromatin undergoes wide-ranging rearrangements that affect the ratio of euchromatin-to-heterochromatin, DNA methylation patterns and the regulation of enhancers and promoters. The molecular machinery underlying this process remains largely unknown. Here, we show that Dppa2 and Dppa4, two thus far poorly characterized mES-specific factors, play a key role in resetting the epigenome to a pluripotent configuration. They function as a heterodimer, are induced in late reprogramming intermediates, and are required for reprogramming. When overexpressed with OSKM factors, Dppa2/4 yield reprogramming efficiencies exceeding 75% of the starting culture and accelerate reprogramming kinetics, generating iPSCs in as little as 4 days. When chromatinbound, Dppa2/4 initiate global chromatin decompaction via the DNA damage response pathway, which subsequently activates mES promoters and enhancers and enables an efficient progression to pluripotency. Our work provides critical insights into how the epigenome is remodeled during cell fate transitions. Overall design: Transcriptional regulation by the Dppa2 and Dppa4 investigated by ChIP-Seq and RNA-Seq

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Hernandez C, Wang Z, Ramazanov B, Tang Y, Mehta S, Dambrot C, Lee YW, Tessema K, Kumar I, Astudillo M, Neubert TA, Guo S, Ivanova NB