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Dynamic enhancer partitioning instructs activation of a growth-related gene during exit from naïve pluripotency

Authors
  • Greenberg, Maxim Van Cleef
  • Teissandier, Aurélie
  • Walter, Marius
  • Noordermeer, Daan
  • BOURC'HIS, Deborah
Publication Date
Jan 01, 2019
Identifiers
DOI: 10.7554/eLife.44057
PMID: 30990414
OAI: oai:HAL:hal-02171009v1
Source
HAL-CEA
Keywords
Language
English
License
Unknown
External links

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.

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