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EZH2 Regulates the Developmental Timing of Effectors of the Pre-Antigen Receptor Checkpoints

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EZH2 Regulates the Developmental Timing of Effectors of the Pre-Antigen Receptor Checkpoints EZH2 Regulates the Developmental Timing of Effectors of the Pre-Antigen Receptor Checkpoints This information is current as Jennifer A. Jacobsen, Jennifer Woodard, Malay Mandal, of October 2, 2021. Marcus R. Clark, Elizabeth T. Bartom, Mikael Sigvardsson and Barbara L. Kee J Immunol published online 10 May 2017 http://www.jimmunol.org/content/early/2017/05/10/jimmun ol.1700319 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/05/10/jimmunol.170031 Material 9.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on October 2, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published May 10, 2017, doi:10.4049/jimmunol.1700319 The Journal of Immunology EZH2 Regulates the Developmental Timing of Effectors of the Pre-Antigen Receptor Checkpoints Jennifer A. Jacobsen,* Jennifer Woodard,* Malay Mandal,† Marcus R. Clark,*,† Elizabeth T. Bartom,‡ Mikael Sigvardsson,x and Barbara L. Kee*,{ The histone methyltransferase EZH2 is required for B and T cell development; however, the molecular mechanisms underlying this requirement remain elusive. In a murine model of lymphoid-specific EZH2 deficiency we found that EZH2 was required for proper development of adaptive, but not innate, lymphoid cells. In adaptive lymphoid cells EZH2 prevented the premature expres- sion of Cdkn2a and the consequent stabilization of p53, an effector of the pre–Ag receptor checkpoints. Deletion of Cdkn2a in EZH2-deficient lymphocytes prevented p53 stabilization, extended lymphocyte survival, and restored differentiation resulting in the generation of mature B and T lymphocytes. Our results uncover a crucial role for EZH2 in adaptive lymphocytes to control the developmental timing of effectors of the pre–Ag receptor checkpoints. The Journal of Immunology, 2017, 198: 000–000. Downloaded from he lymphoid arm of the immune system is divided into produced before they progress to subsequent stages of differentia- innate and adaptive components that can be distinguished tion and before they undergo further proliferation (2). The mecha- T by the mechanisms they use to detect and respond to in- nisms that ensure appropriate activation of Ag-receptor checkpoints vading pathogens (1). Innate lymphoid cells (ILCs) express an after initiation of V(D)J recombination are not well understood. array of germline-encoded receptors that rapidly induce cytokine V(D)J recombination occurs in an ordered manner in which pro- production or cytotoxic functions when triggered by invading B lymphocytes rearrange their IgH gene (Igh) segments before they http://www.jimmunol.org/ pathogens. In contrast, adaptive lymphoid cells detect pathogens progress to the pre-B cell stage, where they rearrange the L chain using Ag-specific receptors that are generated through the RAG- (Igl) genes (3). Similarly, Tcrb rearrangements occur in double dependent assembly of variable (V), diversity (D), and joining (J) negative (DN) three thymocytes followed by Tcra rearrangements gene segments. The process of V(D)J recombination creates at the double positive (DP) stage of T cell development. The unique receptors on each developing B or T lymphocyte, but it also production of a functional IgH chain or TCRb-chain is ensured produces many defective receptors and puts the cells at risk for by a checkpoint in which these proteins, as part of a pre-BCR or oncogenic transformation. Therefore, developing B and T cells must pre-TCR, impart a signal to the cell that inhibits the p53-induced apoptosis pathway (4, 5). Destabilizing p53 is a critical require- pass through “checkpoints” to ensure that a functional receptor is by guest on October 2, 2021 ment for progression beyond the pre–Ag receptor checkpoint as revealed in mice lacking the pre-TCR (i.e., Rag12/2 or Cd3g2/2 *Committee on Immunology, The University of Chicago, Chicago, IL 60637; †Division of Rheumatology, Department of Medicine, The University of Chicago, mice), which fail b-selection but can by-pass this checkpoint Chicago, IL 60637; ‡Northwestern University, Chicago, IL 60611; xDepartment of when Trp53 (p53) is deleted or mutated (6, 7). Stabilization of p53 { Molecular Hematology, Lund University, 22184 Lund, Sweden; and Department of prevents B and T cell development beyond the pre–Ag receptor Pathology, The University of Chicago, Chicago, IL 60637 checkpoints, as evidenced in mice lacking genes that directly ORCIDs: 0000-0002-5354-6870 (J.A.J.); 0000-0002-0451-3896 (M.M.); 0000-0002- 5618-2582 (E.T.B.). regulate p53 at the transcriptional (WIP1 (8, 9), MYSM1 (10)), Received for publication March 1, 2017. Accepted for publication April 17, 2017. posttranscriptional (CNOT (11)), translational (RPL22 (12, 13), MIZ1 (14, 15)), or posttranslational (YY1 (16–18), BCL11A (19), This work was supported by grants from the National Institutes of Health (R21 AI109233, R01 AI106352) and a pilot project award from the University of Chicago NIR (20)) levels. Remarkably, B and T cell maturation are sub- Comprehensive Cancer Center (P30 CA014599). J.A.J. was supported by Medical stantially restored in these mice upon deletion of p53. Scientist Training Grant T32 GM007281, J.W. was supported by a fellowship from the Leukemia and Lymphoma Society, and B.L.K. was a Leukemia and Lymphoma p53 is exquisitely regulated in lymphocyte progenitors to ensure Society scholar. that it is only transiently expressed at the time of pre–Ag receptor J.A.J. performed experiments, analyzed and interpreted data, and wrote the manu- selection. Although Trp53 mRNA is constitutively transcribed in script; J.W. and M.S. performed experiments; E.T.B. analyzed data; M.M. and M.R.C. pro-B lymphocytes prior to the requirement for pre-BCR selec- provided advice and chromatin immunoprecipitation sequencing data; B.L.K. di- rected the studies, analyzed and interpreted data, and wrote the paper. tion, p53 is not present due to its rapid degradation by the pro- teasome (21). Degradation of p53 is initiated by the ubiquitin The RNA-sequencing data presented in this article have been submitted to the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) under accession number ligase MDM2 (21). At the pre-BCR checkpoint p53 becomes GSE97462. stabilized when MDM2 is inhibited by p19ARF, which is one of Address correspondence and reprint requests to Dr. Barbara L. Kee, Department of two proteins produced from the Cdkn2a gene (22). Transcription Pathology, The University of Chicago, 924 East 57th Street, JFK Room 318, Chi- of Cdkn2a is induced, in part, by the transcription factor BACH2, cago, IL 60637. E-mail address: [email protected] which is expressed in pro-B lymphocytes; but how transcription of The online version of this article contains supplemental material. Cdkn2a is restrained until the pre-BCR checkpoint is not well Abbreviations used in this article: BM, bone marrow; ChIP, chromatin immunopre- cipitation; CLP, common lymphoid progenitor; DKO, double knockout; DN, double understood (5, 23). Signaling through the pre-BCR restores p53 negative; DP, double positive; ETP, early thymic progenitor; H3K27, histone 3 lysine degradation by inducing the activity of the transcriptional re- 27; ILC, innate lymphoid cell; ILC2P, ILC2 progenitor; PI, propidium iodide; PRC2, pressor BCL6, which displaces BACH2 from the Cdkn2a gene polycomb repressive complex 2; qPCR, quantitative PCR; WT, wild-type. and silences Cdkn2a/p19 expression thereby allowing the sur- Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 vival of appropriately signaled pre-B cells. The proper activation www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700319 2 EZH2 REGULATES PRE–Ag RECEPTOR CHECKPOINT TIMING and repression of the pre–Ag receptor checkpoints are essential (eBioscience). H3K27me3 was detected with a secondary anti-rabbit IgG for proper lymphocyte development and prevent lymphocyte directly conjugated to PE. Samples were analyzed on an LSRII or Fortessa transformation. and cells were sorted on a FACS Aria running FACS Diva software. Analysis was carried out in FlowJo. The developmental programs of innate and adaptive lymphocytes are established by lineage defining transcription factors in col- Cell culture laboration with chromatin modifying complexes that regulate Cells were maintained in OPTI-MEM media supplemented with 10% FBS, genome accessibility. Polycomb repressive complex 2 (PRC2) is a 80 mM 2-ME, 100 U/ml penicillin, 100 mg/ml streptomycin, and 29.2 mg/ml protein complex that contains the histone methyltransferase EZH2, glutamine. Pro-B cultures were initiated with B220+ cells magnetically which catalyzes the methylation of histone 3 lysine 27 (H3K27) enriched from the BM by MACS-based separation (Miltenyi Biotec) and were supplemented with IL-7 (produced from J558 cells stably transduced (24). H3K27me3 is found at the promoters and along the gene with an IL-7 expression vector) (30). NK cell cultures were initiated with bodies of repressed genes, and at the promoters of genes that are DX5+ cells enriched from the spleen and were supplemented with IL-2 poised for activation (25). Inducible deletion of the SET domain (1000 IU/ml; National Institutes of Health Reagents Program). GSK126 of EZH2 in all hematopoietic cells results in arrested lymphocyte (10 mM) and DZnep (5 mM) were added to wild-type (WT) pro-B cultures development at the pro-B cell stage (26) and DN3 stage (27).
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