A Recurrent Network Involving the Transcription Factors PU.1 and Gfi1 Orchestrates Innate and Adaptive Immune Cell Fates
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The transcription factor PU.1, encoded by the Sfpi1 gene, functions in a graded manner to regulate macrophage versus B cell generation; its higher concentration favors the macrophage fate. We demonstrated that Gfi1 reciprocally promoted B cell fate choice at the expense of myeloid progeny. Gfi1(-/-) multipotential progenitors (MPPs) were unable to constrain the expression of PU.1 because Gfi1 functioned to repress the Sfpi1 gene by displacing PU.1 from positive autoregulatory elements. Attenuating a transcriptional module composed of PU.1 and Egr suppressed the B lineage developmental defects of Gfi1(-/-) MPPs. Finally Ikaros, a transcription factor required for B cell development, promoted Gfi1 and antagonized PU.1 expression in MPPs. Our results reveal that a core transcriptional regulatory network used for directing cell fate choice in the innate immune system has been co-opted by Ikaros to orchestrate B lymphocyte generation. These findings have important implications for the evolution of the adaptive immune system.
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Gfi1 likely represses the Irf8, Klf4 and Zeb2 genes by interrupting positive regulation by PU.1 and Irf8, similar to its antagonism of PU.1 on the Spi1 gene.
“Thus Gfi1 likely represses the Irf8, Klf4 and Zeb2 genes by interrupting positive regulation by PU.1 and Irf8, similar to its antagonism of PU.1 on the Spi1 gene29.”
From Single-cell analysis of mixed-lineage states leading to a binary cell fate choice (2016) · cites this paper as [29]
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Cites
Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages
Scott, E. W., Simon, M. C., Anastasi, J., & Singh, H. (1994) · Science · doi:10.1126/science.8079170 · Cited by 1,532 · see citing works
Self-citationIdentification of Flt3+ Lympho-Myeloid Stem Cells Lacking Erythro-Megakaryocytic Potential
Adolfsson, J., Månsson, R., Buza-Vidas, N., Hultquist, A., Liuba, K., Jensen, C. T., Bryder, D., Yang, L., Borge, O. J., Thorén, L., et al. (2005) · Cell · doi:10.1016/j.cell.2005.02.013 · Cited by 1,229 · see citing works
Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities
McKercher, S. R., Torbett, B. E., Anderson, K. L., Henkel, G. W., Vestal, D. J., Baribault, H., Klemsz, M., Feeney, A. J., Wu, G. E., Paige, C. J., et al. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00949.x · Cited by 1,130 · see citing works
Regulation of B lymphocyte and macrophage development by graded expression of PU.1
DeKoter, R. P., & Singh, H. (2000) · Science · doi:10.1126/science.288.5470.1439 · Cited by 749 · see citing works
Self-citationMultilineage Transcriptional Priming and Determination of Alternate Hematopoietic Cell Fates
Laslo, P., Spooner, C. J., Warmflash, A., Lancki, D. W., Lee, H.-J., Sciammas, R., Gantner, B. N., Dinner, A. R., & Singh, H. (2006) · Cell · doi:10.1016/j.cell.2006.06.052 · Cited by 632 · see citing works
Self-citationWang, J., Nichogiannopoulou, A., Wu, L. J., Sun, L., Sharpe, A. H., Bigby, M. E., & Georgopoulos, K. (1996) · Immunity · doi:10.1016/s1074-7613(00)80269-1 · Cited by 614 · see citing works
Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells
Hock, H., Hamblen, M. J., Rooke, H. M., Schindler, J. W., Saleque, S., Fujiwara, Y., & Orkin, S. H. (2004) · Nature · doi:10.1038/nature02994 · Cited by 541 · see citing works
Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1.
Rosenbauer, F., Wagner, K., Kutok, J. L., Iwasaki, H., Le Beau, M. M., Okuno, Y., Akashi, K., Fiering, S., & Tenen, D. G. (2004) · Nature Genetics · doi:10.1038/ng1361 · Cited by 506 · see citing works
Swiatek, P. J., & Gridley, T. (1993) · Genes & Development · doi:10.1101/gad.7.11.2071 · Cited by 468 · see citing works
Intrinsic Requirement for Zinc Finger Transcription Factor Gfi-1 in Neutrophil Differentiation
Hock, H., Hamblen, M. J., Rooke, H. M., Traver, D., Bronson, R. T., Cameron, S., & Orkin, S. H. (2003) · Immunity · doi:10.1016/s1074-7613(02)00501-0 · Cited by 384 · see citing works
Dahl, R., Walsh, J. C., Lancki, D., Laslo, P., Iyer, S. R., Singh, H., & Simon, M. C. (2003) · Nature Immunology · doi:10.1038/ni973 · Cited by 380 · see citing works
Self-citationLaiosa, C. V., Stadtfeld, M., Xie, H., de Andres-Aguayo, L., & Graf, T. (2006) · Immunity · doi:10.1016/j.immuni.2006.09.011 · Cited by 351 · see citing works
Transcription factor Gfi1 regulates self‐renewal and engraftment of hematopoietic stem cells
Zeng, H., Yücel, R., Kosan, C., Klein‐Hitpaß, L., & Möröy, T. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600419 · Cited by 328 · see citing works
Dynamic regulation of PU.1 expression in multipotent hematopoietic progenitors
Nutt, S. L., Metcalf, D., D'Amico, A., Polli, M., & Wu, L. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20041535 · Cited by 325 · see citing works
Early hematopoietic lineage restrictions directed by Ikaros
Yoshida, T., Ng, S. Y., Zúñiga‐Pflücker, J. C., & Georgopoulos, K. (2006) · Nature Immunology · doi:10.1038/ni1314 · Cited by 324 · see citing works
PU.1 Regulates Expression of the Interleukin-7 Receptor in Lymphoid Progenitors
DeKoter, R. P., Lee, H.-J., & Singh, H. (2002) · Immunity · doi:10.1016/s1074-7613(02)00269-8 · Cited by 319 · see citing works
Self-citationInflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1
Karsunky, H., Zeng, H., Schmidt, T., Zevnik, B., Kluge, R., Schmid, K. W., Dührsen, U., & Möröy, T. (2002) · Nature Genetics · doi:10.1038/ng831 · Cited by 315 · see citing works
DeKoter, R. P., Walsh, J. C., & Singh, H. (1998) · The EMBO Journal · doi:10.1093/emboj/17.15.4456 · Cited by 296 · see citing works
Self-citationRegulation of the helix-loop-helix proteins, E2A and Id3, by the Ras-ERK MAPK cascade
Bain, G., Cravatt, C. B., Loomans, C. J. M., Alberola‐Ila, J., Hedrick, S. Μ., & Murre, C. (2001) · Nature Immunology · doi:10.1038/84273 · Cited by 287 · see citing works
Walsh, J. C., DeKoter, R. P., Lee, H.-J., Smith, E. D., Lancki, D. W., Gurish, M. F., Friend, D. S., Stevens, R. L., Anastasi, J., & Singh, H. (2002) · Immunity · doi:10.1016/s1074-7613(02)00452-1 · Cited by 262 · cited 5× · see citing works
“580 Immunity 31, 576–586, October 16, 2009 ª2009 Elsevier Inc. we performed ChIP-on-chip assays by using a promoter array to identify PU.1 target genes in OHT-induced PUER cells.”
MethodInfluentialSelf-citationRegulation of B cell fate commitment and immunoglobulin heavy-chain gene rearrangements by Ikaros
Reynaud, D., Demarco, I. A., Reddy, K. L., Schjerven, H., Bertolino, E., Chen, Z., Smale, S. T., Winandy, S., & Singh, H. (2008) · Nature Immunology · doi:10.1038/ni.1626 · Cited by 261 · see citing works
Self-citationDETERMINANTS OF LYMPHOID-MYELOID LINEAGE DIVERSIFICATION
Laiosa, C. V., Stadtfeld, M., & Graf, T. (2006) · Annual Review of Immunology · doi:10.1146/annurev.immunol.24.021605.090742 · Cited by 260 · see citing works
MOLECULAR GENETICS OF T CELL DEVELOPMENT
Rothenberg, E. V., & Taghon, T. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.23.021704.115737 · Cited by 256 · see citing works
Pongubala, J. M. R., Northrup, D. L., Lancki, D. W., Medina, K. L., Treiber, T., Bertolino, E., Thomas, M., Grosschedl, R., Allman, D., & Singh, H. (2008) · Nature Immunology · doi:10.1038/ni1555 · Cited by 250 · see citing works
Self-citationNg, S. Y., Yoshida, T., Zhang, J., & Georgopoulos, K. (2009) · Immunity · doi:10.1016/j.immuni.2009.01.014 · Cited by 245 · see citing works
Assembling a Gene Regulatory Network for Specification of the B Cell Fate
Medina, K. L., Pongubala, J. M. R., Reddy, K. L., Lancki, D. W., DeKoter, R. P., Kieslinger, M., Grosschedl, R., & Singh, H. (2004) · Developmental Cell · doi:10.1016/j.devcel.2004.08.006 · Cited by 240 · see citing works
Self-citationRosenbauer, F., Owens, B. M., Yu, L., Tumang, J. R., Steidl, U., Kutok, J. L., Clayton, L. K., Wagner, K., Scheller, M., Iwasaki, H., et al. (2006) · Nature Genetics · doi:10.1038/ng1679 · Cited by 237 · see citing works
E2A Proteins Promote Development of Lymphoid-Primed Multipotent Progenitors
Dias, S., Månsson, R., Gurbuxani, S. K., Sigvardsson, M., & Kee, B. L. (2008) · Immunity · doi:10.1016/j.immuni.2008.05.015 · Cited by 226 · see citing works
E Protein Function in Lymphocyte Development
Quong, M. W., Romanow, W. J., & Murre, C. (2002) · Annual Review of Immunology · doi:10.1146/annurev.immunol.20.092501.162048 · Cited by 196 · see citing works
Contingent gene regulatory networks and B cell fate specification
Singh, H., Medina, K. L., & Pongubala, J. M. R. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0500480102 · Cited by 185 · see citing works
Self-citationAnderson, M. K., Weiss, A. H., Hernandez-Hoyos, G., Dionne, C. J., & Rothenberg, E. V. (2002) · Immunity · doi:10.1016/s1074-7613(02)00277-7 · Cited by 182 · cited 2× · see citing works
“1 has been shown to inhibit early T cell development (Anderson et al., 2002) and promote macrophage differentiation (Laiosa et al.”
BackgroundPotential Autoregulation of Transcription Factor PU.1 by an Upstream Regulatory Element
Okuno, Y., Huang, G., Rosenbauer, F., Evans, E. K., Radomska, H. S., Iwasaki, H., Akashi, K., Moreau-Gachelin, F., Li, Y., Zhang, P., et al. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.7.2832-2845.2005 · Cited by 174 · see citing works
Yücel, R., Karsunky, H., Klein‐Hitpaß, L., & Möröy, T. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20021417 · Cited by 165 · see citing works
Regulation of Lymphoid versus Myeloid Fate 'choice' by the Transcription Factor Mef2c
Stehling-Sun, S., Dade, J., Nutt, S. L., DeKoter, R. P., & Camargo, F. D. (2009) · Nature Immunology · doi:10.1038/ni.1694 · Cited by 125 · see citing works
Yücel, R., Kosan, C., Heyd, F., & Möröy, T. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400808200 · Cited by 122 · see citing works
Notch/Delta signaling constrains reengineering of pro-T cells by PU.1
Franco, C. B., Scripture-Adams, D. D., Proekt, I., Taghon, T., Weiss, A. H., Yui, M. A., Adams, S. L., Diamond, R. A., & Rothenberg, E. V. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601188103 · Cited by 109 · see citing works
Thymocyte Development in Early Growth Response Gene 1-Deficient Mice
Bettini, M. L., Xi, H., Milbrandt, J., et al. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.4.1713 · Cited by 103 · see citing works
Gene regulatory networks directing myeloid and lymphoid cell fates within the immune system
Laslo, P., Pongubala, J. M. R., Lancki, D. W., & Singh, H. (2008) · Seminars in Immunology · doi:10.1016/j.smim.2008.08.003 · Cited by 102 · see citing works
Self-citationKrysinska, H., Hoogenkamp, M., Ingram, R., Wilson, N., Tagoh, H., Laslo, P., Singh, H., & Bonifer, C. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01915-06 · Cited by 102 · see citing works
Self-citationThe Transcriptional Repressor GFI-1 Antagonizes PU.1 Activity through Protein-Protein Interaction
Dahl, R. E., Iyer, S. R., Owens, K., Cuylear, D. D., & Simon, M. C. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m607613200 · Cited by 93 · see citing works
Ebf1-mediated down-regulation of Id2 and Id3 is essential for specification of the B cell lineage
Thal, M. A., Carvalho, T. L., He, T., Kim, H., Gao, H., Hagman, J. R., & Klug, C. A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802550106 · Cited by 93 · see citing works
Zarebski, A. P., Velu, C. S., Baktula, A. M., Bourdeau, T., Horman, S. R., Basu, S., Bertolone, S. J., Horwitz, M. S., Hildeman, D. A., Trent, J. O., et al. (2008) · Immunity · doi:10.1016/j.immuni.2007.12.020 · Cited by 91 · see citing works
Singh, H. (1996) · Current Opinion in Immunology · doi:10.1016/s0952-7915(96)80053-7 · Cited by 77 · see citing works
Self-citationPU.1, a Shared Transcriptional Regulator of Lymphoid and Myeloid Cell Fates
SINGH, H., DEKOTER, R. P., & WALSH, J. C. (1999) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.1999.64.13 · Cited by 66 · see citing works
Self-citationConditional, floxed allele of the Krox20 gene
Taillebourg, E., Buart, S., & Charnay, P. (2002) · genesis · doi:10.1002/gene.10062 · Cited by 40 · see citing works
Zou, G.-M., Chen, J., Yöder, M. C., Wu, W., & Rowley, J. D. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506218102 · Cited by 39 · see citing works
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Wilson, N. K., Foster, S. D., Wang, X., Knezevic, K., Schütte, J., Kaimakis, P., Chilarska, P. M., Kinston, S., Ouwehand, W. H., Dzierzak, E., et al. (2010) · Cell stem cell · doi:10.1016/j.stem.2010.07.016 · Cited by 728 · see citing works
Emerging properties of animal gene regulatory networks
Davidson, E. H. (2010) · Nature · doi:10.1038/nature09645 · Cited by 579 · see citing works
Single-cell analysis of mixed-lineage states leading to a binary cell fate choice
Olsson, A., Venkatasubramanian, M., Chaudhri, V. K., Aronow, B. J., Salomonis, N., Singh, H., & Grimes, H. L. (2016) · Nature · doi:10.1038/nature19348 · Cited by 476 · see citing works
Self-citationCarotta, S., Dakic, A., D'Amico, A., Pang, S. H. M., Greig, K. T., Nutt, S. L., & Wu, L. (2010) · Immunity · doi:10.1016/j.immuni.2010.05.005 · Cited by 279 · see citing works
Positive Feedback Between PU.1 and the Cell Cycle Controls Myeloid Differentiation
Kueh, H. Y., Champhekar, A., Nutt, S. L., Elowitz, M. B., & Rothenberg, E. V. (2013) · Science · doi:10.1126/science.1240831 · Cited by 273 · see citing works
The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis
Burda, P., Laslo, P., & Stopka, T. (2010) · Leukemia · doi:10.1038/leu.2010.104 · Cited by 184 · see citing works
Self-citationTranscription factor networks in B-cell differentiation link development to acute lymphoid leukemia
Somasundaram, R., Prasad, M. A. J., Ungerbäck, J., & Sigvardsson, M. (2015) · Blood · doi:10.1182/blood-2014-12-575688 · Cited by 135 · see citing works
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Turkistany, S. A., & DeKoter, R. P. (2011) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-011-0147-9 · Cited by 96 · see citing works
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Mak, K. S., Funnell, A. P. W., Pearson, R. C. M., & Crossley, M. (2011) · International Journal of Cell Biology · doi:10.1155/2011/808524 · Cited by 77 · see citing works
Pang, S. H. M., de Graaf, C. A., Hilton, D. J., Huntington, N. D., Carotta, S., Wu, L., & Nutt, S. L. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01264 · Cited by 60 · see citing works
“Interestingly, Gfi1 expression was increased in PU.1-deficient LSK cells, suggesting that PU.1 also functions at some level to repress Gfi1 (Figure 5A).”
BackgroundInfluentialZarnegar, M. A., Chen, J., & Rothenberg, E. V. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00354-10 · Cited by 52 · see citing works
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Kusy, S., Gault, N., Ferri, F., Lewandowski, D., Barroca, V., Jaracz-Ros, A., Losson, R., & Romeo, P.-H. (2011) · Cell stem cell · doi:10.1016/j.stem.2011.02.005 · Cited by 47 · see citing works
Design principles of cell-state-specific enhancers in hematopoiesis
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Ahmed, N., Etzrodt, M., Dettinger, P., Kull, T., Loeffler, D., Hoppe, P. S., Chavez, J. S., Zhang, Y., Camargo Ortega, G., Hilsenbeck, O., et al. (2022) · Journal of Experimental Medicine · doi:10.1084/jem.20202490 · Cited by 9 · see citing works
- Authors
- Spooner, C. J., Cheng, J. X., Pujadas, E., Laslo, P., & Singh, H.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Chicago (US)
- Corresponding author
- Singh, Harinder
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 31
- Issue
- 4
- Pages
- 576-586
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC4373467
- OpenAlex
- W2001764493
- Cited by
- 188
- References
- 46
- Citations by year
- 2026: 1 · 2025: 10 · 2024: 4 · 2023: 8 · 2022: 5 · 2021: 12 · 2020: 3 · 2019: 8 · 2018: 12 · 2017: 13 · 2016: 16 · 2015: 12 · 2014: 12 · 2013: 18 · 2012: 15
- FWCI
- 7.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences (P50GM081892)
- National Institute of Diabetes and Digestive and Kidney Diseases (T90DK070076)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- PU.1, GFI1, Ikaros, transcriptional regulatory networks, B cell development, multipotent progenitors, Egr transcription factors, transcriptional repression, myeloid progenitor cells
- MeSH terms
- Proto-Oncogene Protein Spi-1, Animals, B-Lymphocytes, DNA-Binding Proteins, Immunity, Active, Immunity, Innate, Macrophages, Promoter Regions, Genetic, Proto-Oncogene Proteins, Transcription Factors, Trans-Activators, Mice, Knockout, Mice, Ikaros Transcription Factor, Gene Regulatory Networks
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