Dppa2/4 Facilitate Epigenetic Remodeling During Reprogramming to Pluripotency

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2018 Aug 28

PMID 30146411

Citations 38

Authors

Charles Hernandez

Zheng Wang

Bulat Ramazanov

Yin Tang

Sameet Mehta

Cheryl Dambrot

Yu-Wei Lee

Kaleab Tessema

Ishan Kumar

Michael Astudillo

Thomas A Neubert

Shangqin Guo

Natalia B Ivanova

Affiliations

Soon will be listed here.

Abstract

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.

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