Roles of H3K27me2 and H3K27me3 Examined during Fate Specification of Embryonic Stem Cells
Aster H. Juan,
Stan Wang,
Kyung Dae Ko,
Hossein Zare,
Pei-Fang Tsai,
Xuesong Feng,
Karinna O. Vivanco,
Anthony M. Ascoli,
Gustavo Gutierrez-Cruz,
Jordan Krebs,
Simone Sidoli,
Adam L. Knight,
Roger A. Pedersen,
Benjamin A. Garcia,
Rafael Casellas,
Jizhong Zou,
Vittorio Sartorelli
Affiliations
Aster H. Juan
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA; Corresponding author
Stan Wang
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA; Wellcome Trust/Cancer Research UK Gurdon Institute, Tennis Court Road, Cambridge CB2 1QN, UK; Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK
Kyung Dae Ko
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA
Hossein Zare
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA
Pei-Fang Tsai
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA
Xuesong Feng
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA
Karinna O. Vivanco
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA; Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Anthony M. Ascoli
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA
Gustavo Gutierrez-Cruz
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA
Jordan Krebs
Genomics and Immunity, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA
Simone Sidoli
Epigenetics Program, Department of Biochemistry and Biophysics, Perlman School of Medicine, University of Pennsylvania, Philadelphia 19104 PA, USA
Adam L. Knight
Synaptic Function Section, The Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Roger A. Pedersen
Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK; The Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, Downing Street, Cambridge, CB2 3EH, UK
Benjamin A. Garcia
Epigenetics Program, Department of Biochemistry and Biophysics, Perlman School of Medicine, University of Pennsylvania, Philadelphia 19104 PA, USA
Rafael Casellas
Genomics and Immunity, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA
Jizhong Zou
iPSC Core Facility, Center for Molecular Medicine, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
Vittorio Sartorelli
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA; Corresponding author
Summary: The polycomb repressive complex 2 (PRC2) methylates lysine 27 of histone H3 (H3K27) through its catalytic subunit Ezh2. PRC2-mediated di- and tri-methylation (H3K27me2/H3K27me3) have been interchangeably associated with gene repression. However, it remains unclear whether these two degrees of H3K27 methylation have different functions. In this study, we have generated isogenic mouse embryonic stem cells (ESCs) with a modified H3K27me2/H3K27me3 ratio. Our findings document dynamic developmental control in the genomic distribution of H3K27me2 and H3K27me3 at regulatory regions in ESCs. They also reveal that modifying the ratio of H3K27me2 and H3K27me3 is sufficient for the acquisition and repression of defined cell lineage transcriptional programs and phenotypes and influences induction of the ESC ground state. : Juan et al. use genome editing to subtly modify H3K27 methylation states (H3K27me2/H3K27me3) and report that such perturbation influences the ability of ESCs to differentiate into preferential cell lineages and acquire a “ground state.” Keywords: polycomb proteins, H3K27 methylation, embryonic stem cells
