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

Abstract
Data availability
Article and author information
Metrics

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.

The following data sets were generated

(2019) Sequencing data from Dynamic enhancer partitioning instructs activation of a growth-related gene during exit from naïve pluripotency
NCBI Gene Expression Omnibus, GSE121405.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE121405

The following previously published data sets were used

(2017) Liz transcription is required for evicting H3K27me3 marks at the Gpr1/Zdbf2 locus through the deposition of DNA methylation marks.
NCBI Gene Expression Omnibus, GSE79549.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE79549
(2016) An epigenetic switch ensures transposon repression upon acute loss of DNA methylation in ES cells
NCBI Gene Expression Omnibus, GSE71593.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE71593
1. Wu J
2. Huang B
3. Chen H
4. Yin Q et al
(2016) The landscape of accessible chromatin in mammalian pre-implantation embryos
NCBI Gene Expression Omnibus, GSE66390.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE66390
1. Liu X
2. Wang C
3. Liu W
4. Li J et al
(2016) Distinct features in establishing H3K4me3 and H3K27me3 in pre-implantation embryos
NCBI Gene Expression Omnibus, GSE73952.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE73952
(2014) Reorganization of enhancer patterns in transition from naïve to primed pluripotency
NCBI Gene Expression Omnibus, GSE56138.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE56138
1. Bao S
2. Tang WW
3. Wu B
4. Kim S et al
(2017) Enhancing the Potency of Mouse Embryonic Stem Cells
NCBI Gene Expression Omnibus, GSE99494.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE99494

Article and author information

Author details

Maxim Van Cleef Greenberg

Unité de Génétique et Biologie du Développement, Institut Curie, Paris, France

For correspondence
maxim.greenberg@curie.fr

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-9935-8763
Aurélie Teissandier

Department of Genetics and Developmental Biology, Institut Curie, Paris, France

Competing interests
No competing interests declared.
Marius Walter

The Buck Institute for Research on Aging, Novato, United States

Competing interests
No competing interests declared.
Daan Noordermeer

Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, Gif sur Yvette, France

Competing interests
No competing interests declared.
Deborah Bourc'his

Unité de Génétique et Biologie du Développement, Institut Curie, Paris, France

For correspondence
Deborah.Bourchis@curie.fr

Competing interests
Deborah Bourc'his, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0001-9499-7291

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

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.