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Cited by 25Hematopoietic Stem Cell TransplantationBlood disorders and treatmentsToxic Organic Pollutants Impact

Conditional deletion of Ahr alters gene expression profiles in hematopoietic stem cells

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Bennett, John A., Singh, Kameshwar P., Welle, Stephen L., Boule, Lisbeth A., Lawrence, B. Paige, Gasiewicz, Thomas A.·2018·PLOS ONE
DOI 10.1371/journal.pone.0206407PMC PMC6214519
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Abstract

The aryl hydrocarbon receptor (AHR) is a ligand activated bHLH transcription factor that belongs to the Per-Arnt-Sim (PAS) superfamily of proteins involved in mediating responses to cellular environment regulating normal physiological and developmental pathways. The AHR binds a broad range of naturally derived and synthetic compounds, and plays a major role in mediating effects of certain environmental chemicals. Although our understanding of the physiological roles of the AHR in the immune system is evolving, there is little known about its role in hematopoiesis and hematopoietic diseases. Prior studies demonstrated that AHR null (AHR-KO) mice have impaired hematopoietic stem cell (HSC) function; they develop myeloproliferative changes in peripheral blood cells, and alterations in hematopoietic stem and progenitor cell populations in the bone marrow. We hypothesized mice lacking AHR expression only within hematopoietic cells (AHRVav1 mice) would develop similar changes. However, we did not observe a complete phenocopy of AHR-KO and AHRVav1 animals at 2 or 18 months of age. To illuminate the signaling mechanisms underlying the alterations in hematopoiesis observed in these mice, we sorted a population of cells highly enriched for HSC function (LSK cells: CD34-CD48-CD150+) and performed microarray analyses. Ingenuity Pathway and Gene Set Enrichment Analyses revealed that that loss of AHR within HSCs alters several gene and signaling networks important for HSC function. Differences in gene expression networks among HSCs from AHR-KO and AHRVav1 mice suggest that AHR in bone marrow stromal cells also contributes to HSC function. In addition, numerous studies have suggested a role for AHR in both regulation of hematopoietic cells, and in the development of blood diseases. More work is needed to define what these signals are, and how they act upon HSCs.

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  • AHR has cell-specific roles in lymphocytes, intestinal epithelial cells, keratinocytes, Langerhans cells, and hematopoietic stem cells.

    “Subsequent examination of this mouse crossed to various Cre models has unveiled a cell specific role for AHR in lymphocytes, intestinal epithelial cells, keratinocytes, Langerhans cells, and hematopoietic stem cells to name a few (Bennett et al., 2018; Haas et al., 2016; Hong et al., 2020; Li et al., 2018; Metidji et al., 2018)”

    From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Bennett et al., 2018

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Research works printed but not linked: 49

  1. [1]Akada H, Akada S, Hutchison RE, Sakamoto K, Wagner KU, Mohi G. Critical role of Jak2 in the maintenance and function of adult hematopoietic stem cells. Stem cells (Dayton, Ohio). 2014; 32(7): 1878– 89. 10.1002/stem.1711 24677703 PMC4063883 · DOI
  2. [2]Singh KP, Wyman A, Casado FL, Garrett RW, Gasiewicz TA. Treatment of mice with the Ah receptor agonist and human carcinogen dioxin results in altered numbers and function of hematopoietic stem cells. Carcinogenesis. 2009; 30(1): 11– 9. 10.1093/carcin/bgn224 18820284 PMC2639033 · DOI
  3. [3]Casado FL, Singh KP, Gasiewicz TA. Aryl hydrocarbon receptor activation in hematopoietic stem/progenitor cells alters cell function and pathway-specific gene modulation reflecting changes in cellular trafficking and migration. Molecular pharmacology. 2011; 80(4): 673– 82. 10.1124/mol.111.071381 21791576 PMC3187533 · DOI
  4. [4]Garrett RW, Gasiewicz TA. The aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin alters the circadian rhythms, quiescence, and expression of clock genes in murine hematopoietic stem and progenitor cells. Molecular pharmacology. 2006; 69(6): 2076– 83. 10.1124/mol.105.021006 16556773 · DOI
  5. [5]Sun D, Luo M, Jeong M, Rodriguez B, Xia Z, Hannah R, et al Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell stem cell. 2014; 14(5): 673– 88. 10.1016/j.stem.2014.03.002 24792119 PMC4070311 · DOI · Paper page
  6. [6]Singh KP, Garrett RW, Casado FL, Gasiewicz TA. Aryl hydrocarbon receptor-null allele mice have hematopoietic stem/progenitor cells with abnormal characteristics and functions. Stem cells and development. 2011; 20(5): 769– 84. 10.1089/scd.2010.0333 20874460 PMC3128774 · DOI
  7. [7]Singh KP, Bennett JA, Casado FL, Walrath JL, Welle SL, Gasiewicz TA. Loss of aryl hydrocarbon receptor promotes gene changes associated with premature hematopoietic stem cell exhaustion and development of a myeloproliferative disorder in aging mice. Stem cells and development. 2014; 23(2): 95– 106. 10.1089/scd.2013.0346 24138668 PMC3887405 · DOI
  8. [8]Hayes MD, Ovcinnikovs V, Smith AG, Kimber I, Dearman RJ. The aryl hydrocarbon receptor: differential contribution to T helper 17 and T cytotoxic 17 cell development. PloS one. 2014; 9(9): e106955 10.1371/journal.pone.0106955 25203682 PMC4159274 · DOI
  9. [9]Esser C, Rannug A. The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology. Pharmacological reviews. 2015; 67(2): 259– 79. 10.1124/pr.114.009001 25657351 · DOI · Paper page
  10. [10]Ahrenhoerster LS, Leuthner TC, Tate ER, Lakatos PA, Laiosa MD. Developmental exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin attenuates later-life Notch1-mediated T cell development and leukemogenesis. Toxicology and applied pharmacology. 2015; 283(2): 99– 108. 10.1016/j.taap.2014.12.017 25585350 PMC4331100 · DOI
  11. [11]Winans B, Nagari A, Chae M, Post CM, Ko CI, Puga A, et al Linking the Aryl Hydrocarbon Receptor with Altered DNA Methylation Patterns and Developmentally Induced Aberrant Antiviral CD8+ T Cell Responses. Journal of immunology (Baltimore, Md: 1950). 2015. PMC4402273 25810390
  12. [12]Kawajiri K, Fujii-Kuriyama Y. The aryl hydrocarbon receptor: a multifunctional chemical sensor for host defense and homeostatic maintenance. Experimental animals. 2017; 66(2): 75– 89. 10.1538/expanim.16-0092 27980293 PMC5411294 · DOI
  13. [13]Esser C. The immune phenotype of AhR null mouse mutants: not a simple mirror of xenobiotic receptor over-activation. Biochemical pharmacology. 2009; 77(4): 597– 607. 10.1016/j.bcp.2008.10.002 18983984 · DOI
  14. [14]Boulais PE, Frenette PS. Making sense of hematopoietic stem cell niches. Blood. 2015. PMC4408288 25762174
  15. [15]Boyd AL, Salci KR, Shapovalova Z, McIntyre BA, Bhatia M. Nonhematopoietic cells represent a more rational target of in vivo hedgehog signaling affecting normal or acute myeloid leukemia progenitors. Experimental hematology. 2013; 41(10): 858– 69 e4. 10.1016/j.exphem.2013.05.287 23747997 · DOI
  16. [16]Charbord P, Pouget C, Binder H, Dumont F, Stik G, Levy P, et al A systems biology approach for defining the molecular framework of the hematopoietic stem cell niche. Cell stem cell. 2014; 15(3): 376– 91. 10.1016/j.stem.2014.06.005 25042701 · DOI
  17. [17]Hooker RA, Chitteti BR, Egan PH, Cheng YH, Himes ER, Meijome T, et al Activated leukocyte cell adhesion molecule (ALCAM or CD166) modulates bone phenotype and hematopoiesis. Journal of musculoskeletal & neuronal interactions. 2015; 15(1): 83– 94. 25730656 PMC4439374
  18. [18]Gori JL, Butler JM, Chan YY, Chandrasekaran D, Poulos MG, Ginsberg M, et al Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells. The Journal of clinical investigation. 2015; 125(3): 1243– 54. 10.1172/JCI79328 25664855 PMC4362238 · DOI
  19. [19]Iyer S, Brooks R, Gumbleton M, Kerr WG. SHIP1-Expressing Mesenchymal Stem Cells Regulate Hematopoietic Stem Cell Homeostasis and Lineage Commitment During Aging Stem cells and development 2014. PMC4403265 25525673
  20. [20]Walisser JA, Glover E, Pande K, Liss AL, Bradfield CA. Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types. Proceedings of the National Academy of Sciences of the United States of America. 2005; 102(49): 17858– 63. 10.1073/pnas.0504757102 16301529 PMC1308889 · DOI · Paper page
  21. [21]de Boer J, Williams A, Skavdis G, Harker N, Coles M, Tolaini M, et al Transgenic mice with hematopoietic and lymphoid specific expression of Cre. European journal of immunology. 2003; 33(2): 314– 25. 10.1002/immu.200310005 12548562 · DOI · Paper page
  22. [22]Wheeler JL, Martin KC, Lawrence BP. Novel cellular targets of AhR underlie alterations in neutrophilic inflammation and inducible nitric oxide synthase expression during influenza virus infection. Journal of immunology (Baltimore, Md: 1950). 2013; 190(2): 659– 68. PMC3538960 23233726
  23. [23]Boule LA, Burke CG, Jin GB, Lawrence BP. Aryl hydrocarbon receptor signaling modulates antiviral immune responses: ligand metabolism rather than chemical source is the stronger predictor of outcome. Scientific reports. 2018; 8(1): 1826 10.1038/s41598-018-20197-4 29379138 PMC5789012 · DOI
  24. [24]Jin GB, Winans B, Martin KC, Lawrence BP. New insights into the role of the aryl hydrocarbon receptor in the function of CD11c(+) cells during respiratory viral infection. European journal of immunology. 2014; 44(6): 1685– 98. 10.1002/eji.201343980 24519489 PMC4048642 · DOI
  25. [25]Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods (San Diego, Calif). 2001; 25(4): 402– 8. 10.1006/meth.2001.1262 11846609 · DOI · Paper page
  26. [26]Georgiades P, Ogilvy S, Duval H, Licence DR, Charnock-Jones DS, Smith SK, et al VavCre transgenic mice: a tool for mutagenesis in hematopoietic and endothelial lineages. Genesis (New York, NY: 2000). 2002; 34(4): 251– 6. 10.1002/gene.10161 12434335 · DOI
  27. [27]Till JE, McCulloch EA. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. 1961. Radiat Res. 2012; 178(2): AV3– 7. 22870977
  28. [28]Lu H, Cui W, Klaassen CD. Nrf2 protects against 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced oxidative injury and steatohepatitis. Toxicology and applied pharmacology. 2011; 256(2): 122– 35. 10.1016/j.taap.2011.07.019 21846477 PMC3183285 · DOI
  29. [29]Bell DR, Van Zant G. Stem cells, aging, and cancer: inevitabilities and outcomes. Oncogene. 2004; 23(43): 7290– 6. 10.1038/sj.onc.1207949 15378089 · DOI
  30. [30]Beerman I, Bhattacharya D, Zandi S, Sigvardsson M, Weissman IL, Bryder D, et al Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proceedings of the National Academy of Sciences of the United States of America. 2010; 107(12): 5465– 70. 10.1073/pnas.1000834107 20304793 PMC2851806 · DOI · Paper page
  31. [31]Chambers SM, Shaw CA, Gatza C, Fisk CJ, Donehower LA, Goodell MA. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol. 2007; 5(8): e201 10.1371/journal.pbio.0050201 17676974 PMC1925137 · DOI
  32. [33]Gordon SM, Alon N, Buchwald M. FANCC, FANCE, and FANCD2 form a ternary complex essential to the integrity of the Fanconi anemia DNA damage response pathway. J Biol Chem. 2005; 280(43): 36118– 25. 10.1074/jbc.M507758200 16127171 · DOI
  33. [34]Zipfel PF, Skerka C. Complement factor H and related proteins: an expanding family of complement-regulatory proteins? Immunol Today. 1994; 15(3): 121– 6. 10.1016/0167-5699(94)90155-4 8172644 · DOI
  34. [35]Liebermann DA, Gregory B, Hoffman B. AP-1 (Fos/Jun) transcription factors in hematopoietic differentiation and apoptosis. Int J Oncol. 1998; 12(3): 685– 700. 9472112
  35. [36]Lee SY, Yoon J, Lee MH, Jung SK, Kim DJ, Bode AM, et al The role of heterodimeric AP-1 protein comprised of JunD and c-Fos proteins in hematopoiesis. J Biol Chem. 2012; 287(37): 31342– 8. 10.1074/jbc.M112.387266 22822070 PMC3438963 · DOI
  36. [37]Contador-Troca M, Alvarez-Barrientos A, Barrasa E, Rico-Leo EM, Catalina-Fernandez I, Menacho-Marquez M, et al The dioxin receptor has tumor suppressor activity in melanoma growth and metastasis. Carcinogenesis. 2013; 34(12): 2683– 93. 10.1093/carcin/bgt248 23843039 · DOI
  37. [39]Vezina CM, Lin TM, Peterson RE. AHR signaling in prostate growth, morphogenesis, and disease. Biochemical pharmacology. 2009; 77(4): 566– 76. 10.1016/j.bcp.2008.09.039 18977204 PMC2918267 · DOI
  38. [40]Chiaro CR, Morales JL, Prabhu KS, Perdew GH. Leukotriene A4 metabolites are endogenous ligands for the Ah receptor. Biochemistry. 2008; 47(32): 8445– 55. 10.1021/bi800712f 18616291 · DOI
  39. [41]Denison MS, Nagy SR. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu Rev Pharmacol Toxicol. 2003; 43: 309– 34. 10.1146/annurev.pharmtox.43.100901.135828 12540743 · DOI · Paper page
  40. [42]Kawasaki H, Chang HW, Tseng HC, Hsu SC, Yang SJ, Hung CH, et al A tryptophan metabolite, kynurenine, promotes mast cell activation through aryl hydrocarbon receptor. Allergy. 2014; 69(4): 445– 52. 10.1111/all.12346 24397465 · DOI
  41. [43]Nguyen LP, Hsu EL, Chowdhury G, Dostalek M, Guengerich FP, Bradfield CA. D-amino acid oxidase generates agonists of the aryl hydrocarbon receptor from D-tryptophan. Chem Res Toxicol. 2009; 22(12): 1897– 904. 10.1021/tx900043s 19860415 PMC2923838 · DOI
  42. [44]Schlafli AM, Torbett BE, Fey MF, Tschan MP. BIRC6 (APOLLON) is down-regulated in acute myeloid leukemia and its knockdown attenuates neutrophil differentiation. Experimental hematology & oncology. 2012; 1(1): 25. 23211188 PMC3514096
  43. [45]Unnisa Z, Singh KP, Henry EC, Donegan CL, Bennett JA, Gasiewicz TA. Aryl Hydrocarbon Receptor Deficiency in an Exon 3 Deletion Mouse Model Promotes Hematopoietic Stem Cell Proliferation and Impacts Endosteal Niche Cells. Stem cells international. 2016; 2016: 4536187 10.1155/2016/4536187 27366154 PMC4913018 · DOI
  44. [46]Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, et al Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004; 118(2): 149– 61. 10.1016/j.cell.2004.07.004 15260986 · DOI
  45. [47]Schepers K, Hsiao EC, Garg T, Scott MJ, Passegue E. Activated Gs signaling in osteoblastic cells alters the hematopoietic stem cell niche in mice. Blood. 2012; 120(17): 3425– 35. 10.1182/blood-2011-11-395418 22859604 PMC3482855 · DOI
  46. [48]Narasimhan SD, Yen K, Bansal A, Kwon ES, Padmanabhan S, Tissenbaum HA. PDP-1 links the TGF-beta and IIS pathways to regulate longevity, development, and metabolism. PLoS genetics. 2011; 7(4): e1001377 10.1371/journal.pgen.1001377 21533078 PMC3080858 · DOI
  47. [49]Vercherat C, Chung TK, Yalcin S, Gulbagci N, Gopinadhan S, Ghaffari S, et al Stra13 regulates oxidative stress mediated skeletal muscle degeneration. Human molecular genetics. 2009; 18(22): 4304– 16. 10.1093/hmg/ddp383 19679564 · DOI
  48. [50]Lam K, Zhang DE. RUNX1 and RUNX1-ETO: roles in hematopoiesis and leukemogenesis. Frontiers in bioscience (Landmark edition). 2012; 17: 1120– 39. PMC3433167 22201794
  49. [51]Kong CS, Cao H, Kwok S, Nguyen CM, Jordan RC, Beaudry VG, et al Loss of the p53/p63 target PERP is an early event in oral carcinogenesis and correlates with higher rate of local relapse. Oral surgery, oral medicine, oral pathology and oral radiology. 2013; 115(1): 95– 103. 10.1016/j.oooo.2012.10.017 23217540 PMC3523282 · DOI

Cited by

Sorted by citations

Authors
Bennett, J. A., Singh, K. P., Welle, S. L., Boule, L. A., Lawrence, B. P., & Gasiewicz, T. A.
Affiliations
University of Rochester Medicine (US)
Corresponding author
Gasiewicz, Thomas A.
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2018-11-02
Volume
13
Issue
11
Pages
e0206407
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0206407
PMC
PMC6214519
OpenAlex
W2899468957
Cited by
25
References
2
Citations by year
2026: 2 · 2025: 1 · 2024: 4 · 2023: 1 · 2022: 3 · 2021: 6 · 2020: 4 · 2019: 4
FWCI
2.51
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
National Institutes of Health (P30 ES01247, T32ES07026, ES023068, ES04862)
Topics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
Keywords
aryl hydrocarbon receptor, hematopoietic stem cells, conditional gene deletion, Vav1, hematopoiesis, gene expression profiling, mesenchymal stem cells, myeloproliferative neoplasms, AhR knockout mice, LSK cells, environmental chemical exposure
MeSH terms
Animals, Hematopoietic Stem Cells, Phenotype, Signal Transduction, Gene Deletion, Receptors, Aryl Hydrocarbon, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Transcriptome

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