1. H2A.Z.1 Monoubiquitylation Antagonizes BRD2 to Maintain Poised Chromatin in ESCs
- Author
-
Surface, Lauren E., Fields, Paul A., Subramanian, Vidya, Behmer, Russell, Udeshi, Namrata, Peach, Sally E., Carr, Steven A., Jaffe, Jacob D., Boyer, Laurie, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Surface, Lauren E., Fields, Paul A., Subramanian, Vidya, Behmer, Russell, and Boyer, Laurie
- Subjects
0301 basic medicine ,animal structures ,Chromosomal Proteins, Non-Histone ,Cellular differentiation ,Polycomb-Group Proteins ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Histones ,Mice ,03 medical and health sciences ,Polycomb-group proteins ,Animals ,Cell Lineage ,Cell Self Renewal ,Promoter Regions, Genetic ,lcsh:QH301-705.5 ,Regulation of gene expression ,Genetics ,Ubiquitination ,Gene Expression Regulation, Developmental ,Cell Differentiation ,Mouse Embryonic Stem Cells ,Chromatin ,3. Good health ,Bromodomain ,030104 developmental biology ,Histone ,lcsh:Biology (General) ,embryonic structures ,biology.protein ,PRC1 ,Protein Binding ,Transcription Factors ,Bivalent chromatin - 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[superscript K3R3]). We show that H2A.Z.1[superscript 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[superscript 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., National Institutes of Health (U.S.) (Pre-doctoral Training Grant T32GM007287), Massachusetts Institute of Technology. School of Science (Fellowship in Cancer Research), National Cancer Institute (U.S.) (Core Grant Award P30-CA14051), National Heart, Lung, and Blood Institute. Bench to Bassinet Program (U01HL098179), Massachusetts Life Sciences Center
- Published
- 2016
- Full Text
- View/download PDF