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Bhlhe40 and Bhlhe41 transcription factors regulate alveolar macrophage self‐renewal and identity
Open accessAbstract
Tissues in multicellular organisms are populated by resident macrophages, which perform both generic and tissue-specific functions. The latter are induced by signals from the microenvironment and rely on unique tissue-specific molecular programs requiring the combinatorial action of tissue-specific and broadly expressed transcriptional regulators. Here, we identify the transcription factors Bhlhe40 and Bhlhe41 as novel regulators of alveolar macrophages (AMs)-a population that provides the first line of immune defense and executes homeostatic functions in lung alveoli. In the absence of these factors, AMs exhibited decreased proliferation that resulted in a severe disadvantage of knockout AMs in a competitive setting. Gene expression analyses revealed a broad cell-intrinsic footprint of Bhlhe40/Bhlhe41 deficiency manifested by a downregulation of AM signature genes and induction of signature genes of other macrophage lineages. Genome-wide characterization of Bhlhe40 DNA binding suggested that these transcription factors directly repress the expression of lineage-inappropriate genes in AMs. Taken together, these results identify Bhlhe40 and Bhlhe41 as key regulators of AM self-renewal and guardians of their identity.
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“The transcription factors BHLHE40/41 play roles in immune cell differentiation and function.”
From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [51]
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Metadata
- Authors
- Rauschmeier, R., Gustafsson, C., Reinhardt, A., A‐Gonzalez, N., Tortola, L., Cansever, D., Subramanian, S., Taneja, R., Rossner, M. J., Sieweke, M. H., Greter, M., Månsson, R., Busslinger, M., & Kreslavsky, T.
- Affiliations
- Research Institute of Molecular Pathology (AT)
- Karolinska Institutet (SE)
- Karolinska University Hospital (SE)
- ETH Zurich (CH)
- University of Zurich (CH)
- Centre National de la Recherche Scientifique (FR)
- National University of Singapore (SG)
- Ludwig-Maximilians-Universität München (DE)
- Corresponding author
- Kreslavsky, Taras
- ORCID
- Venue
- The EMBO Journal
- Published
- 2019-08-15
- Volume
- 38
- Issue
- 19
- Pages
- e101233-e101233
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC6769426
- OpenAlex
- W2967087236
- Cited by
- 102
- References
- 73
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 21 · 2023: 15 · 2022: 18 · 2021: 14 · 2020: 6 · 2019: 3
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- HAL (submittedVersion)
- Funders
- Austrian Science Fund (P28841)
- Vetenskapsrådet (2017‐01118)
- Österreichische Forschungsförderungsgesellschaft (FFG‐852936)
- Agence Nationale de la Recherche (ANR‐11‐BSV3‐0026)
- Fondation pour la Recherche Médicale (DEQ. 20110421320)
- H2020 European Research Council (695093 MacAge)
- Deutsche Forschungsgemeinschaft (RE 4264/1‐1)
- Cancerfonden (CAN 2018/710)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- BHLHE40, BHLHE41, alveolar macrophages, macrophage self-renewal, macrophage identity, transcription factors, lineage-specific gene expression, DNA binding, competitive fitness, lung homeostasis, macrophage differentiation
- MeSH terms
- Cell Self Renewal, Acetylation, Animals, Cell Differentiation, Cell Survival, Histones, Organ Specificity, Phenotype, Down-Regulation, Macrophages, Alveolar, Sequence Analysis, RNA, Homeodomain Proteins, Gene Expression Profiling, Cell Proliferation, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Gene Knockdown Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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