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

The EMBO journal 2019 Oct 01

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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. © 2019 The Authors.

Citation

René Rauschmeier, Charlotte Gustafsson, Annika Reinhardt, Noelia A-Gonzalez, Luigi Tortola, Dilay Cansever, Sethuraman Subramanian, Reshma Taneja, Moritz J Rossner, Michael H Sieweke, Melanie Greter, Robert Månsson, Meinrad Busslinger, Taras Kreslavsky. Bhlhe40 and Bhlhe41 transcription factors regulate alveolar macrophage self-renewal and identity. The EMBO journal. 2019 Oct 01;38(19):e101233