Bhlhe40 and Bhlhe41 transcription factors regulate alveolar macrophage self-renewal and identity
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
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.
Details
Original language | English |
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Article number | e101233 |
Journal | The EMBO journal |
Volume | 38 |
Issue number | 19 |
Publication status | Published - 1 Oct 2019 |
Peer-reviewed | Yes |
External IDs
PubMedCentral | PMC6769426 |
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Scopus | 85070783115 |
Keywords
Keywords
- Acetylation, Animals, Basic Helix-Loop-Helix Transcription Factors/genetics, Cell Differentiation, Cell Proliferation, Cell Self Renewal, Cell Survival, Down-Regulation, Gene Expression Profiling/methods, Gene Knockdown Techniques, Histones/metabolism, Homeodomain Proteins/genetics, Macrophages, Alveolar/cytology, Mice, Organ Specificity, Phenotype, Sequence Analysis, RNA