PU.1 Level-Directed Chromatin Structure Remodeling at the Irf8 Gene Drives Dendritic Cell Commitment
Open accessAbstract
Dendritic cells (DCs) are essential regulators of immune responses; however, transcriptional mechanisms that establish DC lineage commitment are poorly defined. Here, we report that the PU.1 transcription factor induces specific remodeling of the higher-order chromatin structure at the interferon regulatory factor 8 (Irf8) gene to initiate DC fate choice. An Irf8 reporter mouse enabled us to pinpoint an initial progenitor stage at which DCs separate from other myeloid lineages in the bone marrow. In the absence of Irf8, this progenitor undergoes DC-to-neutrophil reprogramming, indicating that DC commitment requires an active, Irf8-dependent escape from alternative myeloid lineage potential. Mechanistically, myeloid Irf8 expression depends on high PU.1 levels, resulting in local chromosomal looping and activation of a lineage- and developmental-stage-specific cis-enhancer. These data delineate PU.1 as a concentration-dependent rheostat of myeloid lineage selection by controlling long-distance contacts between regulatory elements and suggest that specific higher-order chromatin remodeling at the Irf8 gene determines DC differentiation.
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PU.1 directly induces IRF8 transcription by binding to its enhancer and promoter.
“PU.1 directly induces IRF8 transcription by binding to its enhancer and promoter [50], while IRF8 reciprocally enhances PU.1 expression by targeting an upstream regulatory element of the PU.1 gene [29, 39].”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [50]
In “PU.1 Binding Is Necessary for −50 kb Enhancer Activity and Induces Chromatin Remodeling” (page unavailable), the paper reports PU.1 binding at the Irf8 enhancer and describes PU.1 as a direct activator of Irf8 expression. It reports enhancer–promoter contact, but does not establish that PU.1 also binds the promoter; that part of the attributed mechanism is unsupported. (LLM, conf=0.88)
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Cites
Hildner, K., Edelson, B. T., Purtha, W. E., Diamond, M., Matsushita, H., Kohyama, M., Calderon, B., Schraml, B. U., Unanue, E. R., Diamond, M. S., et al. (2008) · Science · doi:10.1126/science.1164206 · Cited by 2,081 · see citing works
Looping and Interaction between Hypersensitive Sites in the Active β-globin Locus
Tolhuis, B., Palstra, R.-J., Splinter, E., Grosveld, F., & de Laat, W. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00781-5 · Cited by 1,344 · see citing works
Cis-regulatory elements: Molecular mechanisms and evolutionary processes underlying divergence
Wittkopp, P. J., & Kalay, G. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3095 · Cited by 1,231 · see citing works
Quantitative analysis of chromosome conformation capture assays (3C-qPCR)
Hagège, H., Klous, P., Braem, C., Splinter, E., Dekker, J., Cathala, G., de Laat, W., & Forné, T. (2007) · Nature Protocols · doi:10.1038/nprot.2007.243 · Cited by 720 · see citing works
Holtschke, T., Löhler, J., Kanno, Y., Fehr, T., Giese, N., Rosenbauer, F., Lou, J., Knobeloch, K.-P., Gabriele, L., Waring, J. F., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81348-3 · Cited by 644 · 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
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 1× · see citing works
“7, NIH 3T3, 416B, PU.1–/–ERT-PU.1, and PU.1–/– cell lines were cultured as described before (Leddin et al., 2011; Walsh et al., 2002).”
MethodRosenbauer, 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
Self-citationPU. 1 is required for myeloid-derived but not lymphoid-derived dendritic cells
Guerriero, A., Langmuir, P. B., Spain, L. M., & Scott, E. W. (2000) · Blood · doi:10.1182/blood.v95.3.879.003k13_879_885 · Cited by 190 · see citing works
Two distinct auto-regulatory loops operate at the PU.1 locus in B cells and myeloid cells
Leddin, M., Perrod, C., Hoogenkamp, M., Ghani, S., Assi, S., Heinz, S., Wilson, N. K., Follows, G., Schönheit, J., Vockentanz, L., et al. (2011) · Blood · doi:10.1182/blood-2010-08-302976 · Cited by 131 · see citing works
Self-citationImmune cell-specific amplification of interferon signaling by the IRF-4/8-PU. 1 complex
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Theisen, D. J., Ferris, S. T., Briseño, C. G., Kretzer, N., Iwata, A., Murphy, K. M., & Murphy, T. L. (2019) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0138 · Cited by 66 · see citing works
Carey, H. A., Hildreth, B. E., Geisler, J. A., Nickel, M. C., Cabrera, J., Ghosh, S., Jiang, Y., Yan, J., Lee, J., Makam, S., et al. (2018) · Bone Research · doi:10.1038/s41413-018-0011-1 · Cited by 40 · see citing works
Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease
Kim, B., Wang, S. S., Kim, J. R., & Kim, J. (2026) · BioEssays · doi:10.1002/bies.70186
- Authors
- Schönheit, J., Kuhl, C., Gebhardt, M. L., Klett, F. F., Riemke, P., Scheller, M., Huang, G., Naumann, R., Leutz, A., Stocking, C., Priller, J., Andrade-Navarro, M. A., & Rosenbauer, F.
- Affiliations
- Max Delbrück Center (DE)
- University of Münster (DE)
- Cincinnati Children's Hospital Medical Center (US)
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- Leibniz Institute of Virology (LIV) (DE)
- Stiftung Charité (DE)
- Corresponding author
- Rosenbauer, Frank
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 3
- Issue
- 5
- Pages
- 1617-1628
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2145034432
- Cited by
- 127
- References
- 11
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 18 · 2020: 13 · 2019: 10 · 2018: 7 · 2017: 11 · 2016: 12 · 2015: 12 · 2014: 14 · 2013: 2
- FWCI
- 5.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Deutsche Krebshilfe
- Centers for Disease Control and Prevention
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- PU.1, IRF8, dendritic cell differentiation, myeloid lineage commitment, chromatin looping, long-range chromatin interactions, myeloid progenitor cells
- MeSH terms
- Interferon Regulatory Factor-8, Proto-Oncogene Protein Spi-1, Animals, Base Sequence, Bone Marrow Cells, Cell Differentiation, Cells, Cultured, Chromatin, Dendritic Cells, Humans, Mice, Inbred C57BL, Promoter Regions, Genetic, Proto-Oncogene Proteins, Trans-Activators, Mice, Knockout, Cell Lineage, Myeloid Cells, Chromatin Assembly and Disassembly, Interferon Regulatory Factors, Mice
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