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

• Published in: The EMBO journal Vol. 38; no. 19; pp. e101233 - n/a
• Main Authors: Rauschmeier, René, Gustafsson, Charlotte, Reinhardt, Annika, A‐Gonzalez, Noelia, Tortola, Luigi, Cansever, Dilay, Subramanian, Sethuraman, Taneja, Reshma, Rossner, Moritz J, Sieweke, Michael H, Greter, Melanie, Månsson, Robert, Busslinger, Meinrad, Kreslavsky, Taras
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2019; Blackwell Publishing Ltd; EMBO Press; John Wiley and Sons Inc
• Subjects: Acetylation; alveolar macrophages; Alveoli; Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Bhlhe40; Bhlhe41; Cell Differentiation; Cell Proliferation; Cell Self Renewal; Cell Survival; Combinatorial analysis; Deoxyribonucleic acid; DNA; Down-Regulation; EMBO19; EMBO44; Gene expression; Gene Expression Profiling - methods; Gene Knockdown Techniques; Genes; Genomes; Histones - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Immune system; Immunology; Life Sciences; Macrophages; Macrophages, Alveolar - cytology; Macrophages, Alveolar - metabolism; Medicin och hälsovetenskap; Mice; Organ Specificity; Phenotype; Regulators; Regulatory sequences; self‐renewal; Sequence Analysis, RNA; Tissues; tissue‐resident macrophages; Transcription factors; self‐renewal; Bhlhe40; Bhlhe41; tissue‐resident macrophages; alveolar macrophages; tissue-resident macrophages; self-renewal
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.2018101233

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. Synopsis Tissue‐specific macrophage programs are controlled by the combinatorial action of tissue‐specific and broadly expressed transcriptional regulators. The newly identified Bhlhe40 and Bhlhe41 transcription factors safeguard alveolar macrophage identity and self‐renewal by repressing “lineage‐inappropriate” genes. Bhlhe40 and Bhlhe41 are required for competitive fitness of alveolar macrophages. Bhlhe40/Bhlhe41‐deficient alveolar macrophages exhibit decreased proliferation associated with upregulation of Maf and Mafb, which negatively regulate macrophage proliferation. Genes normally expressed in other tissue‐resident macrophages are upregulated in Bhlhe40/Bhlhe41‐deficient alveolar macrophages. Bhlhe40 binds to the regulatory elements of many of these genes, and, together with Bhlhe41, limits H3K27 acetylation at these regions. Graphical Abstract Two newly identified transcription factors safeguard identity and self‐renewal of tissue‐specific macrophages in lung alveoli via repression of “lineage‐inappropriate” genes.