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Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis

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Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis This information is current as Jinpeng Li, Sudin Bhattacharya, Jiajun Zhou, Ashwini S. of October 1, 2021. Phadnis-Moghe, Robert B. Crawford and Norbert E. Kaminski J Immunol published online 4 October 2017 http://www.jimmunol.org/content/early/2017/10/04/jimmun ol.1700289 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/10/04/jimmunol.170028 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 1, 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 October 4, 2017, doi:10.4049/jimmunol.1700289 The Journal of Immunology Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis Jinpeng Li,*,† Sudin Bhattacharya,†,‡,x,{ Jiajun Zhou,†,‖ Ashwini S. Phadnis-Moghe,† Robert B. Crawford,†,x and Norbert E. Kaminski†,x Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates biological responses to endogenous and environmental chemical cues. Increasing evidence shows that the AHR plays physiological roles in regulating development, homeo- stasis, and function of a variety of cell lineages in the immune system. However, the role of AHR in human B cell development has not been investigated. Toward this end, an in vitro feeder-free human B cell developmental model system was employed using human cord blood CD34+ hematopoietic stem/progenitor cells. Using this model, we found that AHR activation by the high-affinity ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin significantly suppressed the generation of early B cells and pro-B cells from hematopoietic stem/progenitor cells, indicating the impairment of B cell lineage specification and commitment. Addition of an AHR antagonist Downloaded from reversed 2,3,7,8-tetrachlorodibenzo-p-dioxin–elicited suppression of early B and pro-B cells, suggesting a role of AHR in regu- lating B lymphopoiesis. Gene expression analysis revealed a significant decrease in the messenger RNA level of early B cell factor 1 (EBF1) and paired box 5, two critical transcription factors directing B cell lineage specification and commitment. Additionally, binding of the ligand-activated AHR to the putative dioxin response elements in the EBF1 promoter was demonstrated by EMSAs and chromatin immunoprecipitation analysis, suggesting transcriptional regulation of EBF1 by AHR. Taken together, this study demonstrates a role for the AHR in regulating human B cell development, and it suggests that transcriptional alterations of EBF1 http://www.jimmunol.org/ by the AHR are involved in the underlying mechanism. The Journal of Immunology, 2017, 199: 000–000. irculating human B cells have an average half-life of 18 d between these transcription factors leads to the loss of myeloid (1). As a result, the homeostasis of the peripheral B cell lineage potential and gives rise to common lymphoid progeni- C population requires lifelong replenishment through B tors (CLPs). The next step in B lymphopoiesis is B cell line- lymphopoiesis. The development of B cells from hematopoietic age specification, which involves the expression of genes that stem cells (HSCs) involves stepwise cell fate choices and lineage are functionally important for B cells. One of the critical tran- restrictions. HSCs first generate progenitor cells with limited scription factors that governs the specification of the B cell de- lineage potential, which further differentiate into cells that are velopmental program is early B cell factor 1 (EBF1). EBF1 is by guest on October 1, 2021 irreversibly committed to the B cell lineage. present at low levels in CLPs and is under the regulation of SPI1, A lineage-specific transcription factor network directs B ETS1, and TCF3 (5). Evidence supporting a critical role of EBF1 lymphopoiesis. The lymphoid priming in HSC-derived multi- in B cell development comes from the observation that Ebf1 potent progenitors is governed by transcription factors IKZF1 knockout mice exhibit a complete block in B cell development at (IKAROS), SPI1 (PU.1), and TCF3 (E2A) (2–4). The interplay the CLP-like stage (6). Ectopic expression of Ebf1 can rescue B lymphopoiesis from developmentally arrested multipotent pro- *Genetics Program, Michigan State University, East Lansing, MI 48824; †Institute for genitors due to deletion of PU.1 or Ikaros (7, 8). Additionally, Integrative Toxicology, Michigan State University, East Lansing, MI 48824; x the expression of EBF1 overcomes the block in B lymphopoiesis ‡Biomedical Engineering, Michigan State University, East Lansing, MI 48824; Depart- ment of Pharmacology and Toxicology, Michigan State University, East Lansing, MI imposed by the absence of E2A (9). Moreover, enforced ex- { 48824; Center for Research on Ingredient Safety, Michigan State University, East Lans- pression of EBF1 in HSCs skews development favoring B cell ing, MI 48824; and ‖Microbiology and Molecular Genetics Program, Michigan State University, East Lansing, MI 48824 lineage commitment (10), further suggesting a critical role for ORCIDs: 0000-0001-5433-723X (A.S.P.-M.); 0000-0002-2144-428X (N.E.K.). EBF1 in the regulatory circuitry of B lymphopoiesis. Increased EBF1activatesexpressionofpairedbox5(PAX5),whichre- Received for publication February 23, 2017. Accepted for publication September 12, 2017. ciprocally upregulates EBF1 through a positive feedback loop (5, This work was supported by National Institutes of Health Grants ES002520 and 11). The elevated expression of EBF1 and PAX5 eliminates al- P42004911. ternative cell fates by suppressing non–B cell genes and activates Address correspondence and reprint requests to Dr. Norbert E. Kaminski, Food many B cell–specific genes that confer B cell identity (12–14). Safety and Toxicology Building, Room 165G, 1129 Farm Lane, Michigan State At this stage, cells lose alternative lineage potential and are ir- University, East Lansing, MI 48824. E-mail address: [email protected] reversibly committed to the B cell lineage. The online version of this article contains supplemental material. Aryl hydrocarbon receptor (AHR) is a ligand-activated tran- Abbreviations used in this article: AHR, aryl hydrocarbon receptor; ARNT, AHR nuclear translocator; ChIP, chromatin immunoprecipitation; CLP, common lymphoid scription factor that acts as a sensor of endogenous and exogenous progenitor; DRE, dioxin response element; EBF1, early B cell factor 1; HSC, hema- chemicals. Upon ligand binding the AHR translocates into the topoietic stem cell; HSPC, hematopoietic stem/progenitor cell; HxCDD, 1,2,3,4,7,8- nucleus and heterodimerizes with AHR nuclear translocator hexachlorodibenzo-p-dioxin; MCDD, 1-chlorodibenzo-p-dioxin; PAX5, paired box 5; qPCR, quantitative PCR; SPADE, spanning-tree progression analysis of density- (ARNT) (15, 16). The ligand-activated AHR/ARNT complex normalized events; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TriCDD, 2,3,7- functions as a transcription factor, binding dioxin responsive el- trichlorodibenzo-p-dioxin. ements (DREs) within regulatory regions of target genes to affect Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$35.00 gene expression (17–19). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700289 2 AHR ACTIVATION IMPAIRS HUMAN B LYMPHOPOIESIS TheAHRwasinitiallydiscoveredinanefforttounderstand Materials and Methods how 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a ubiquitous Chemicals environmental contaminant, mediates biological responses TCDD, 1-chlorodibenzo-p-dioxin (MCDD), 2,3,7-trichlorodibenzo-p- (20). Thereafter, owing to its high binding affinity to AHR, dioxin (TriCDD), and 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (HxCDD) TCDD has been widely used as a probe to study AHR biology, were purchased from AccuStandard (New Haven, CT). DMSO and AHR including its role in the immune system (21, 22). Studies uti- antagonist CH223191 were purchased from Sigma-Aldrich (St. Louis, lizing endogenous and exogenous AHR ligands, AHR an- MO). tagonists, and Ahr knockout animal models have suggested CD34+ cells and in vitro cell culture physiological roles for the AHR in regulating various biological + processes, including developmental, homeostatic, and func- Fresh human CD34 HSPCs isolated from cord blood from mixed donors were purchased from AllCells (Emeryville, CA). The in vitro feeder-free tional, in immunocompetent cell populations (23). Examples HSPC culture was modified based on a previous study (35). Specifically, include a role by the AHR in the activation and proliferation CD34+ cells (1 3 104 cells per well in 96-well tissue culture plates) were of HSCs (24, 25), differentiation of Th17 cells and regulatory cultured in RPMI 1640 media (Life Technologies)
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