Mar 12, 2020

Dppa2/4 Counteract De Novo Methylation to Establish a Permissive Epigenome for Development

bioRxiv
Jamie A Hackett, Kristjan Holm Gretarsson

Abstract

Early mammalian development entails genome-wide epigenome remodeling, including DNA methylation erasure and reacquisition, which facilitates developmental competence. To uncover the mechanisms that orchestrate DNA methylation (DNAme) dynamics, we coupled a single-cell ratiometric DNAme reporter with unbiased CRISPR screening in ESC. We identify key genes and regulatory pathways that drive global DNA hypomethylation, and characterise roles for Cop1 and Dusp6. We also identify Dppa2 and Dppa4 as essential safeguards of focal epigenetic states. In their absence, developmental genes and evolutionary-young LINE1 elements, which DPPA2 specifically binds, lose H3K4me3 and gain ectopic de novo DNA methylation in pluripotent cells. Consequently, lineage-associated genes (and LINE1) acquire a repressive epigenetic memory, which renders them incompetent for activation during future lineage-specification. Dppa2/4 thereby sculpt the pluripotent epigenome by facilitating H3K4me3 and bivalency to counteract de novo methylation; a function co-opted by evolutionary young LINE1 to evade epigenetic decommissioning.

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Mentioned in this Paper

DPPA2 gene
Epigenetic Repression
Genome
Genes
DPPA2 protein, human
Genes, Developmental
Ectopic (Qualifier Value)
DPPA2
Genome-Wide Association Study
Epigenetic Process

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