Dppa2/4 Facilitate Epigenetic Remodeling during Reprogramming to Pluripotency

Abstract

<p id="P4">As somatic cells are converted into iPSCs, their chromatin is remodeled to a pluripotent configuration with unique euchromatin-to-heterochromatin ratio, DNA methylation patterns and enhancer/promoter status. The molecular machinery underlying this process is largely unknown. Here, we show that 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 OKSM factors, Dppa2/4 yield reprogramming efficiencies that exceed 80% and accelerate reprogramming kinetics, generating iPSCs in two to four days. When bound to chromatin, Dppa2/4 initiate global chromatin decompaction via the DNA damage response pathway, contribute to down-regulation 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. </p><p id="P5">During cellular reprogramming the epigenome of a somatic cell is reset to a state compatible with pluripotency maintenance. The molecular machinery underlying this process remains poorly defined. Hernandez et al. identify chromatin-associated factors Dppa2 and Dppa4 as the key components mediating the reset of somatic chromatin to a pluripotent configuration. </p><p class="first" id="P6"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/9982e4b1-f6d0-4975-b239-7928126624e1/PubMedCentral/image/nihms-1503298-f0001.jpg"/> </div> </p>