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Cell Rep DOI:10.1016/j.celrep.2015.12.100

H2A.Z.1 Monoubiquitylation Antagonizes BRD2 to Maintain Poised Chromatin in ESCs.

Publication TypeJournal Article
Year of Publication2016
AuthorsSurface, LE, Fields, PA, Subramanian, V, Behmer, R, Udeshi, N, Peach, SE, Carr, SA, Jaffe, JD, Boyer, LA
JournalCell Rep
Date Published2016 Feb 09
KeywordsAnimals, Cell Differentiation, Cell Lineage, Cell Self Renewal, Chromatin, Chromosomal Proteins, Non-Histone, Gene Expression Regulation, Developmental, Histones, Mice, Mouse Embryonic Stem Cells, Polycomb-Group Proteins, Promoter Regions, Genetic, Protein Binding, Ubiquitination

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.


Alternate JournalCell Rep
PubMed ID26804911
PubMed Central IDPMC4764991
Grant ListU01 HL098179 / HL / NHLBI NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States
P30-CA14051 / CA / NCI NIH HHS / United States
T32GM007287 / GM / NIGMS NIH HHS / United States
U01HL098179 / HL / NHLBI NIH HHS / United States