Promoter bivalency favors an open chromatin architecture in embryonic stem cells

Glòria Mas; Enrique Blanco; Cecilia Ballaré; Miriam Sansó; Yannick G. Spill; Deqing Hu; Yuki Aoi; François Le Dily; Ali Shilatifard; Marc A. Marti-Renom; Luciano Di Croce

doi:10.1038/s41588-018-0218-5

Promoter bivalency favors an open chromatin architecture in embryonic stem cells

Glòria Mas, Enrique Blanco, Cecilia Ballaré, Miriam Sansó, Yannick G. Spill, Deqing Hu, Yuki Aoi, François Le Dily, Ali Shilatifard, Marc A. Marti-Renom^*, Luciano Di Croce

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

83 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1452-1462
Number of pages	11
Journal	Nature Genetics
Volume	50
Issue number	10
DOIs	https://doi.org/10.1038/s41588-018-0218-5
State	Published - Oct 1 2018

Funding

This work would not have been possible without F. Stewart and M. Obst (Biotechnology Center, TU Dresden, Germany), who generously provided the C57B1/6 Mll2F/F mouse ESCs. We are indebted to L. Morey and members of the Di Croce laboratory for insightful discussions and critical reading of the manuscript. We thank V. A. Raker for scientific editing, and the CRG Genomics Unit for their help in genomic experiments. This work was partially supported by the European Research Council under the 7th Framework Program FP7/2007\u20132013 (ERC grant agreement 609989) and the European Union\u2019s Horizon 2020 research and innovation programme (grant agreement 676556) to M.A.M.-R. We also acknowledge support of the Spanish Ministry of Economy and Competitiveness (BFU2016-75008-P), Centro de Excelencia Severo Ochoa 2013\u20132017 (SEV-2012-0208), AGAUR, and Fundaci\u00F3 \u2018La Marat\u00F3 de TV3\u2019 to L.D.C. We also acknowledge a JSPS Research Fellowship for Young Scientists to support Y.A. of US National Cancer Institute grant R35CA197569 to A.S.H.

ASJC Scopus subject areas

Genetics

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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.",

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AU - Mas, Glòria

AU - Blanco, Enrique

AU - Ballaré, Cecilia

AU - Sansó, Miriam

AU - Spill, Yannick G.

AU - Hu, Deqing

AU - Aoi, Yuki

AU - Le Dily, François

AU - Shilatifard, Ali

AU - Marti-Renom, Marc A.

AU - Di Croce, Luciano

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Promoter bivalency favors an open chromatin architecture in embryonic stem cells

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