Cited by 102Immune cells in cancerT-cell and B-cell ImmunologyDevelopmental Biology and Gene Regulation

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Bhlhe40 and Bhlhe41 transcription factors regulate alveolar macrophage self‐renewal and identity

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Rauschmeier, René, Gustafsson, Charlotte, Reinhardt, Annika, A‐Gonzalez, Noelia, Tortola, Luigi, Cansever, Dilay, Subramanian, Sethuraman, Taneja, Reshma, Rossner, Moritz J, Sieweke, Michael H, Greter, Melanie, Månsson, Robert, Busslinger, Meinrad, Kreslavsky, Taras·2019·The EMBO Journal

DOI 10.15252/embj.2018101233PMC PMC6769426

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Abstract

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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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: Rauschmeier, René
Gustafsson, Charlotte
Reinhardt, Annika
A‐Gonzalez, Noelia
Tortola, Luigi
Cansever, Dilay
Subramanian, Sethuraman
Taneja, Reshma
Rossner, Moritz J
Sieweke, Michael H
Greter, Melanie
Månsson, Robert
Busslinger, Meinrad
Kreslavsky, Taras
Venue: The EMBO Journal
Publisher: Springer Science and Business Media LLC
Published: 2019-08-15
Volume: 38
Issue: 19
Pages: e101233-e101233
ISSN: 0261-4189 (ISSN-L)
1460-2075
DOI: 10.15252/embj.2018101233
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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

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Bhlhe40 and Bhlhe41 transcription factors regulate alveolar macrophage self‐renewal and identity

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