title: H2A.Z.1 Monoubiquitylation Antagonizes BRD2 to Maintain Poised Chromatin in ESCs.
abstract: Histone variant H2A.Z occupies the promoters of active and poised, bivalent genes in embryonic stem cells (ESCs) to regulate developmental programs, yet how it contributes to these contrasting states is poorly understood. Here, we investigate the function of H2A.Z.1 monoubiquitylation (H2A.Z.1ub) by mutation of the PRC1 target residues (H2A.Z.1(K3R3)). We show that H2A.Z.1(K3R3) is properly incorporated at target promoters in murine ESCs (mESCs), but loss of monoubiquitylation leads to de-repression of bivalent genes, loss of Polycomb binding, and faulty lineage commitment. Using quantitative proteomics, we find that tandem bromodomain proteins, including the BET family member BRD2, are enriched in H2A.Z.1 chromatin. We further show that BRD2 is gained at de-repressed promoters in H2A.Z.1(K3R3) mESCs, whereas BRD2 inhibition restores gene silencing at these sites. Together, our study reveals an antagonistic relationship between H2A.Z.1ub and BRD2 to regulate the transcriptional balance at bivalent genes to enable proper execution of developmental programs.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139 USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Surface
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139 USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Fields
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139 USA.
authors.forename: Vidya
authors.initials: V
authors.lastname: Subramanian
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139 USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Behmer
authors.affiliation: Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Namrata
authors.initials: N
authors.lastname: Udeshi
authors.affiliation: Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Sally E
authors.initials: SE
authors.lastname: Peach
authors.affiliation: Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.affiliation: Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Jaffe
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139 USA. Electronic address: lboyer@mit.edu.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Boyer
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D000066673:Cell Self Renewal / Q000235:genetics; D002843:Chromatin / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000378:metabolism*; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D063146:Polycomb-Group Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors; D054875:Ubiquitination; D000092468:Bromodomain Containing Proteins
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D063146:Polycomb-Group Proteins; D014157:Transcription Factors; C490844:Brd2 protein, mouse; D000092468:Bromodomain Containing Proteins; C000611883:H2az1 protein, mouse