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bioRxiv · 10.1101/832873

Dppa2/4 target chromatin bivalency enabling multi-lineage commitment

Eckersley-Maslin, M. A.·Parry, A. J.·Blotenburg, M.·Krueger, C.·Franklin, V. N. R.·Clark, S.·D'Santos, C. S.·Reik, W.
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Abstract

Bivalent chromatin marks developmental promoters in pluripotent cells, yet their targeting and precise impact on lineage commitment remains unclear. We uncover Developmental Pluripotency Associated 2 (Dppa2) and 4 (Dppa4) as epigenetic priming factors, establishing chromatin bivalency. Single-cell transcriptomics and differentiation assays reveal Dppa2/4 double knockout embryonic stem cells fail to exit pluripotency and differentiate efficiently. Dppa2/4 associate with COMPASS and Polycomb complexes and are required to recruit and maintain their binding at a subset of developmentally important bivalent promoters which are characterised by low expression and poised RNA polymerase. Consequently, upon Dppa2/4 knockout, these dependent promoters gain DNA methylation and are unable to be activated upon differentiation. Our findings uncover a novel targeting principle for bivalency to developmental promoters, poising them for future lineage specific activation.

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Eckersley-Maslin, M. A., Parry, A. J., Blotenburg, M., Krueger, C., Franklin, V. N. R., Clark, S., D'Santos, C. S., Reik, W.. 2019-11-06. Dppa2/4 target chromatin bivalency enabling multi-lineage commitment. https://doi.org/10.1101/832873

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