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


  • 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


  • EMBO Journal


  • EMBO J 38 (19): e101233


  • 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.