title: Developmental control of polycomb subunit composition by GATA factors mediates a switch to non-canonical functions.
abstract: Polycomb repressive complex 2 (PRC2) plays crucial roles in transcriptional regulation and stem cell development. However, the context-specific functions associated with alternative subunits remain largely unexplored. Here we show that the related enzymatic subunits EZH1 and EZH2 undergo an expression switch during blood cell development. An erythroid-specific enhancer mediates transcriptional activation of EZH1, and a switch from GATA2 to GATA1 controls the developmental EZH1/2 switch by differential association with EZH1 enhancers. We further examine the in vivo stoichiometry of the PRC2 complexes by quantitative proteomics and reveal the existence of an EZH1-SUZ12 subcomplex lacking EED. EZH1 together with SUZ12 form a non-canonical PRC2 complex, occupy active chromatin, and positively regulate gene expression. Loss of EZH2 expression leads to repositioning of EZH1 to EZH2 targets. Thus, the lineage- and developmental stage-specific regulation of PRC2 subunit composition leads to a switch from canonical silencing to non-canonical functions during blood stem cell specification.
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.|Children's Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.|Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Harvard College, Cambridge, MA 02138, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Xie
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Woojin
authors.initials: W
authors.lastname: Kim
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Jialiang
authors.initials: J
authors.lastname: Huang
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Jordan E
authors.initials: JE
authors.lastname: Taylor
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Pinello
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Glass
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Jaffe
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.|Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
mesh_terms: D001483:Base Sequence; D063646:Carcinogenesis; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D041905:Erythroid Cells / Q000378:metabolism; D050980:GATA Transcription Factors / Q000502:physiology*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D008745:Methylation; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D021122:Protein Subunits
chemical_list: D050980:GATA Transcription Factors; D006657:Histones; D021122:Protein Subunits; C103523:EZH1 protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2