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Cell Stem Cell. 2017 May 4;20(5):689-705.e9. doi: 10.1016/j.stem.2017.02.004. Epub 2017 Mar 9.

PRC2 Facilitates the Regulatory Topology Required for Poised Enhancer Function during Pluripotent Stem Cell Differentiation.

Author information

1
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany.
2
Department of Cell Biology, Erasmus Medical Center, 3015 CN Rotterdam, the Netherlands.
3
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany.
4
Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, 08028 Barcelona, Spain.
5
Center for Biomics, Erasmus Medical Center, 3015 CN Rotterdam, the Netherlands.
6
Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany.
7
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany; Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany. Electronic address: aradaigl@uni-koeln.de.

Abstract

Poised enhancers marked by H3K27me3 in pluripotent stem cells have been implicated in the establishment of somatic expression programs during embryonic stem cell (ESC) differentiation. However, the functional relevance and mechanism of action of poised enhancers remain unknown. Using CRISPR/Cas9 technology to engineer precise genetic deletions, we demonstrate that poised enhancers are necessary for the induction of major anterior neural regulators. Interestingly, circularized chromosome conformation capture sequencing (4C-seq) shows that poised enhancers already establish physical interactions with their target genes in ESCs in a polycomb repressive complex 2 (PRC2)-dependent manner. Loss of PRC2 does not activate poised enhancers or induce their putative target genes in undifferentiated ESCs; however, loss of PRC2 in differentiating ESCs severely and specifically compromises the induction of major anterior neural genes representing poised enhancer targets. Overall, our work illuminates an unexpected function for polycomb proteins in facilitating neural induction by endowing major anterior neural loci with a permissive regulatory topology.

KEYWORDS:

PRC2; anterior neural; differentiation; enhancers; facilitators; permissive; pluripotency; poised; polycomb; topology

PMID:
28285903
DOI:
10.1016/j.stem.2017.02.004
[Indexed for MEDLINE]
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