Cooperation of PU.1 With IRF8 and NFATc1 Defines Chromatin Landscapes During RANKL-Induced Osteoclastogenesis
Open accessAbstract
Receptor activator of nuclear factor κB ligand (RANKL) induces osteoclast (OC) differentiation from bone marrow-derived macrophages (BMMs). The transcription factors nuclear factor of activated T cells 1 (NFATc1) and interferon regulatory factor (IRF) 8 play positive and negative roles, respectively, in this process. However, genomewide mapping of the active cis-regulatory elements regulating OC differentiation has not been performed, and little is known about the global landscape of OC-specific gene regulation. We used chromatin immunoprecipitation and formaldehyde-assisted isolation of regulatory elements followed by sequencing to show that PU.1 transcription factor binding motifs were overrepresented at active cis-regulatory regions in both murine BMMs and OCs, while IRF and NFAT binding motifs were selectively enriched at these regions in BMMs and OCs, respectively. We also found that RANKL induced the downregulation of Irf8 and upregulation of Nfatc1 expression, which was associated with dramatic alterations in histone modification. BMM-specific PU.1 binding sites were observed to overlap with IRF8 binding sites in BMMs, and this also occurred for OC-specific PU.1 binding sites and NFATc1 binding sites in OCs. The expression of genes with IRF8 peaks within BMM-specific PU.1 binding sites was significantly higher in BMMs than in OCs, while that of genes with NFATc1 peaks within OC-specific PU.1 binding sites was significantly higher in OCs than in BMMs. Our results suggest that PU.1 switches its transcription partner from IRF8 to NFATc1 and alters the binding regions during RANKL-induced osteoclastogenesis, which is associated with changes in epigenetic profiles and the control of cell type–specific gene expression. © 2019 American Society for Bone and Mineral Research.
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PU.1 participates in the entire process of osteoclast differentiation and promotes osteoclast commitment and maturity.
“Considering PU.1 participates in the entire process of osteoclast differentiation and promotes osteoclast commitment and maturity of osteoclast33,57,58”
From Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis (2025) · cites this paper as [57]
The Discussion reports PU.1 motifs in precursor macrophages and osteoclasts, and notes that mice lacking PU.1 lack mature osteoclasts. The paper supports a role in osteoclast differentiation, but its findings do not establish that PU.1 promotes commitment or participates in every stage of the process. (LLM, conf=0.82)
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- Authors
- Izawa, N., Kurotaki, D., Nomura, S., Fujita, T., Omata, Y., Yasui, T., Hirose, J., Matsumoto, T., Saito, T., Kadono, Y., Okada, H., Miyamoto, T., Tamura, T., Aburatani, H., & Tanaka, S.
- Affiliations
- Research Center for Advanced Science and Technology, The University of Tokyo (JP)
- Yokohama City University (JP)
- The University of Tokyo (JP)
- Teikyo University Hospital, Mizonokuchi (JP)
- Saitama Medical University (JP)
- Keio University (JP)
- Advanced Medical Research Center, Yokohama City University (JP)
- Corresponding author
- Tanaka, Sakae
- ORCID
- Venue
- Journal of Bone and Mineral Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-02-05
- Volume
- 34
- Issue
- 6
- Pages
- 1143-1154
- ISSN
- 0884-0431 (ISSN-L)
- 1523-4681
- OpenAlex
- W2912764306
- Cited by
- 40
- References
- 45
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 8 · 2023: 3 · 2022: 7 · 2021: 5 · 2020: 7
- FWCI
- 1.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Bone and Mineral Research (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology ((#26253075))
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- PU.1, IRF8, NFATc1, osteoclastogenesis, RANKL, bone marrow-derived macrophages, cis-regulatory elements, transcription factor binding motifs, histone modifications, epigenetic regulation, cell type-specific gene expression, chromatin landscape
- MeSH terms
- Interferon Regulatory Factor-8, Proto-Oncogene Protein Spi-1, Animals, Base Sequence, Binding Sites, Chromatin, Humans, Macrophages, Male, Mice, Inbred C57BL, Osteoclasts, Osteogenesis, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins, Transcription, Genetic, Trans-Activators, Genome, Histone Code, Epigenesis, Genetic, NFATC Transcription Factors, Interferon Regulatory Factors, RANK Ligand
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