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Cited by 46Genomics and Chromatin DynamicsHematopoietic Stem Cell TransplantationAcute Myeloid Leukemia Research

PU.1-c-Jun interaction is crucial for PU.1 function in myeloid development

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Zhao, Xinhui, Bartholdy, Boris, Yamamoto, Yukiya, Evans, Erica K., Alberich-Jordà, Meritxell, Staber, Philipp B., Benoukraf, Touati, Zhang, Pu, Zhang, Junyan, Trinh, Bon Q., Crispino, John D., Hoang, Trang, Bassal, Mahmoud A., Tenen, Daniel G.·2022·Communications Biology
DOI 10.1038/s42003-022-03888-7PMC PMC9474506
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Abstract

The Ets transcription factor PU.1 is essential for inducing the differentiation of monocytes, macrophages, and B cells in fetal liver and adult bone marrow. PU.1 controls hematopoietic differentiation through physical interactions with other transcription factors, such as C/EBPα and the AP-1 family member c-Jun. We found that PU.1 recruits c-Jun to promoters without the AP-1 binding sites. To address the functional importance of this interaction, we generated PU.1 point mutants that do not bind c-Jun while maintaining normal DNA binding affinity. These mutants lost the ability to transactivate a target reporter that requires a physical PU.1-c-Jun interaction, and did not induce monocyte/macrophage differentiation of PU.1-deficient cells. Knock-in mice carrying these point mutations displayed an almost complete block in hematopoiesis and perinatal lethality. While the PU.1 mutants were expressed in hematopoietic stem and early progenitor cells, myeloid differentiation was severely blocked, leading to an almost complete loss of mature hematopoietic cells. Differentiation into mature macrophages could be restored by expressing PU.1 mutant fused to c-Jun, demonstrating that a physical PU.1-c-Jun interaction is crucial for the transactivation of PU.1 target genes required for myeloid commitment and normal PU.1 function in vivo during macrophage differentiation.

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  • The AP-1 factors c-Jun and JunB are critical interacting partners with PU.1 that also regulate myeloid differentiation, including PU.1 expression.

    “Indeed, the AP-1 factors c-Jun and JunB are also critical interacting partners with PU.1 that also regulate myeloid differentiation (including PU.1 expression) (Steidl et al., 2006; Raghav et al., 2018; Zhao et al., 2022).”

    From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Zhao et al., 2022

    The Discussion identifies c-Jun as a direct PU.1 interaction partner, and the Results report that their physical interaction is crucial for early myeloid differentiation (page not provided). The Introduction names JunB as an AP-1 family member, but our copy does not establish JunB as a PU.1 interaction partner or show that either factor regulates PU.1 expression. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Several other transcriptional regulators interact with PU.1, including AP-1 family transcription factors.

    “Moreover, several other transcriptional regulators interact with PU.1, including AP-1 family transcription factors (Steidl et al., 2006; Boasman et al., 2019; Zhao et al., 2022).”

    From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Zhao et al., 2022

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Cited by

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Authors
Zhao, X., Bartholdy, B., Yamamoto, Y., Evans, E. K., Alberich-Jordà, M., Staber, P. B., Benoukraf, T., Zhang, P., Zhang, J., Trinh, B. Q., Crispino, J. D., Hoang, T., Bassal, M. A., & Tenen, D. G.
Affiliations
  • Harvard University (US)
  • Albert Einstein College of Medicine (US)
  • Memorial University of Newfoundland (CA)
  • Northwestern University (US)
  • Institute for Research in Immunology and Cancer (CA)
Corresponding author
  • Bassal, Mahmoud A.
  • Tenen, Daniel G.
ORCID
Venue
Communications Biology
Publisher
Springer Science and Business Media LLC
Published
2022-09-14
Volume
5
Issue
1
Pages
961-961
ISSN
2399-3642 (ISSN-L)
DOI
10.1038/s42003-022-03888-7
PMC
PMC9474506
OpenAlex
W4295763013
Cited by
46
References
24
Citations by year
2026: 11 · 2025: 14 · 2024: 13 · 2023: 8
FWCI
2.86
Type
journal article
Language
en
Open access
Licence
Locations
  • Communications Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Foundation for the National Institutes of Health (1R35CA197697, P01HL131477)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Keywords
PU.1, c-Jun, protein-protein interaction, myeloid development, macrophage differentiation, monocyte differentiation, hematopoiesis, transcriptional activation, AP-1, C/EBPα, hematopoietic stem cells, perinatal lethality, ETS transcription factors
MeSH terms
Animals, Binding Sites, Cell Differentiation, Hematopoiesis, Promoter Regions, Genetic, Proto-Oncogene Proteins c-jun, Transcription Factor AP-1, Mice

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