Bhlhe40 and Bhlhe41 transcription factors regulate alveolar macrophage self-renewal and identity
Authors
- R. Rauschmeier
- C. Gustafsson
- A. Reinhardt
- N. A-Gonzalez
- L. Tortola
- D. Cansever
- S. Subramanian
- R. Taneja
- M.J. Rossner
- M.H. Sieweke
- M. Greter
- R. Månsson
- M. Busslinger
- T. Kreslavsky
Journal
- EMBO Journal
Citation
- EMBO J 38 (19): e101233
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.