biostudies-literatureEckersley-Maslin MACancer Research UKMedical Research CouncilWellcome TrustBiotechnology and Biological Sciences Research Council696-705https://www.ebi.ac.uk/biostudies/studies/S-EPMC7614975biostudies-literatureUnknown27(8)How the epigenetic landscape is established in development is still being elucidated. Here, we uncover developmental pluripotency associated 2 and 4 (DPPA2/4) as epigenetic priming factors that establish a permissive epigenetic landscape at a subset of developmentally important bivalent promoters characterized by low expression and poised RNA-polymerase. Differentiation assays reveal that Dppa2/4 double knockout mouse embryonic stem cells fail to exit pluripotency and differentiate efficiently. DPPA2/4 bind both H3K4me3-marked and bivalent gene promoters and associate with COMPASS- and Polycomb-bound chromatin. Comparing knockout and inducible knockdown systems, we find that acute depletion of DPPA2/4 results in rapid loss of H3K4me3 from key bivalent genes, while H3K27me3 is initially more stable but lost following extended culture. Consequently, upon DPPA2/4 depletion, these promoters gain DNA methylation and are unable to be activated upon differentiation. Our findings uncover a novel epigenetic priming mechanism at developmental promoters, poising them for future lineage-specific activation.Nature structural & molecular biologyEpigenetic priming by Dppa2 and 4 in pluripotency facilitates multi-lineage commitment.PMC7614975BB/K010867/1095645/Z/11/ZMR/M008975/1215912/Z/19/Z24453215912BBS/E/B/000C042222310BBS/E/B/000C0421C9545/A29580BBS/E/B/0000H334BB/T009713/1Krueger CReik WIto YFranklin VNRD'Santos CSBlotenburg MNarita MEckersley-Maslin MAParry AfalseEpigenetic priming by Dppa2 and 4 in pluripotency facilitates multi-lineage commitment.How the epigenetic landscape is established in development is still being elucidated. Here, we uncover developmental pluripotency associated 2 and 4 (DPPA2/4) as epigenetic priming factors that establish a permissive epigenetic landscape at a subset of developmentally important bivalent promoters characterized by low expression and poised RNA-polymerase. Differentiation assays reveal that Dppa2/4 double knockout mouse embryonic stem cells fail to exit pluripotency and differentiate efficiently. DPPA2/4 bind both H3K4me3-marked and bivalent gene promoters and associate with COMPASS- and Polycomb-bound chromatin. Comparing knockout and inducible knockdown systems, we find that acute depletion of DPPA2/4 results in rapid loss of H3K4me3 from key bivalent genes, while H3K27me3 is initially more stable but lost following extended culture. Consequently, upon DPPA2/4 depletion, these promoters gain DNA methylation and are unable to be activated upon differentiation. Our findings uncover a novel epigenetic priming mechanism at developmental promoters, poising them for future lineage-specific activation.2020-01-01T00:00:00Z2020 Aug2025-04-04T02:26:25.579Z2025-04-04T02:26:25.579ZS-EPMC76149753257225510.1038/s41594-020-0443-3