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Nat Genet. 2018 Oct;50(10):1452-1462. doi: 10.1038/s41588-018-0218-5. Epub 2018 Sep 17.

Promoter bivalency favors an open chromatin architecture in embryonic stem cells.

Author information

1
Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
2
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
3
Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
4
CNAG-CRG, Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
5
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
6
Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
7
Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain. martirenom@cnag.crg.eu.
8
CNAG-CRG, Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. martirenom@cnag.crg.eu.
9
Universitat Pompeu Fabra (UPF), Barcelona, Spain. martirenom@cnag.crg.eu.
10
ICREA, Barcelona, Spain. martirenom@cnag.crg.eu.
11
Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain. luciano.dicroce@crg.eu.
12
Universitat Pompeu Fabra (UPF), Barcelona, Spain. luciano.dicroce@crg.eu.
13
ICREA, Barcelona, Spain. luciano.dicroce@crg.eu.

Abstract

In embryonic stem cells (ESCs), developmental gene promoters are characterized by their bivalent chromatin state, with simultaneous modification by MLL2 and Polycomb complexes. Although essential for embryogenesis, bivalency is functionally not well understood. Here, we show that MLL2 plays a central role in ESC genome organization. We generate a catalog of bona fide bivalent genes in ESCs and demonstrate that loss of MLL2 leads to increased Polycomb occupancy. Consequently, promoters lose accessibility, long-range interactions are redistributed, and ESCs fail to differentiate. We pose that bivalency balances accessibility and long-range connectivity of promoters, allowing developmental gene expression to be properly modulated.

PMID:
30224650
DOI:
10.1038/s41588-018-0218-5
[Indexed for MEDLINE]

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