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

Rauschmeier, Rene; Gustafsson, Charlotte; Reinhardt, Annika; A-Gonzalez, Noelia; Tortola, Luigi; Cansever, Dilay; Subramanian, Sethuraman; Taneja, Reshma; Rossner, Moritz J.; Sieweke, Michael H.; Greter, Melanie; Mansson, Robert; Busslinger, Meinrad und Kreslavsky, Taras (2019): Bhlhe40 and Bhlhe41 transcription factors regulate alveolar macrophage self-renewal and identity. In: EMBO Journal, Bd. 38, Nr. 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0261-4189
• Sprache: Englisch