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Bhlhe40 and Bhlhe41 transcription factors regulate alveolar macrophage self‐renewal and identity
Author(s) -
Rauschmeier René,
Gustafsson Charlotte,
Reinhardt Annika,
AGonzalez Noelia,
Tortola Luigi,
Cansever Dilay,
Subramanian Sethuraman,
Taneja Reshma,
Rossner Moritz J,
Sieweke Michael H,
Greter Melanie,
Månsson Robert,
Busslinger Meinrad,
Kreslavsky Taras
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2018101233
Subject(s) - biology , alveolar macrophage , microbiology and biotechnology , transcription factor , macrophage , genetics , gene , in vitro
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 ( AM s)—a population that provides the first line of immune defense and executes homeostatic functions in lung alveoli. In the absence of these factors, AM s exhibited decreased proliferation that resulted in a severe disadvantage of knockout AM s 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 AM s. Taken together, these results identify Bhlhe40 and Bhlhe41 as key regulators of AM self‐renewal and guardians of their identity.