Dynamic enhancer partitioning instructs activation of a growth-related gene during exit from naïve pluripotency
Abstract
During early mammalian development, the chromatin landscape undergoes profound transitions. The Zdbf2 gene-involved in growth control-provides a valuable model to study this window: upon exit from naïve pluripotency and prior to tissue differentiation, it undergoes a switch from a distal to a proximal promoter usage, accompanied by a switch from polycomb to DNA methylation occupancy. Using an embryonic stem cell (ESC) system to mimic this period, we show here that four enhancers contribute to the Zdbf2 promoter switch, concomitantly with dynamic changes in chromatin architecture. In ESCs, the locus is partitioned to facilitate enhancer contacts with the distal Zdbf2 promoter. Relieving the partition enhances proximal Zdbf2 promoter activity, as observed during differentiation or with genetic mutants. Importantly, we show that 3D regulation occurs upstream of the polycomb and DNA methylation pathways. Our study reveals the importance of multi-layered regulatory frameworks to ensure proper spatio-temporal activation of developmentally important genes.
Data availability
Sequencing data have been deposited in GEO under accession code GSE121405.
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Article and author information
Author details
Funding
H2020 European Research Council (Cog EpiRepro)
- Deborah Bourc'his
European Molecular Biology Organization (LTF 457-2013)
- Maxim Van Cleef Greenberg
Fondation ARC pour la Recherche sur le Cancer (Post-doc Fellowship)
- Maxim Van Cleef Greenberg
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Greenberg et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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