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| Status |
Public on Jul 30, 2019 |
| Title |
Bhlhe40 and Bhlhe41 transcription factors regulate alveolar macrophage self-renewal and identity |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Tissues in multicellular organisms are ‘serviced’ by resident macrophages, which perform both generic and tissue-specific functions. The latter relies on unique tissue-specific molecular programs induced by signals from the microenvironment and executed through a 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.
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| Overall design |
RNA-seq comparison of Bhlhe40–/–Bhlhe41–/– and wild-type alveolar (steady-state and from mixed bone marrow chimeras) and peritoneal (steady-state) macrophages (2 biological replicates per condition); H3K27ac ChIP-seq comparison of Bhlhe40–/–Bhlhe41–/– and wild-type alveolar macrophages (steady-state; 2 biological replicates per condition); ChIP-seq characterization of Bhlhe40 DNA binding in WT alveolar macrophages (single experiment) with ‘mock’ precipitation sample without antibody but with streptavidin sepharose magnetic beads used to generate the control library (single experiment).
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| Contributor(s) |
Rauschmeier R, Gustafsson C, Reinhardt A, A-Gonzalez N, Tortola L, Cansever D, Subramanian S, Taneja R, Rossner MJ, Sieweke MH, Greter M, Månsson R, Busslinger M, Kreslavsky T |
| Citation(s) |
31414712 |
| |
| Submission date |
Jul 29, 2019 |
| Last update date |
Oct 30, 2019 |
| Contact name |
Taras Kreslavsky |
| E-mail(s) |
taras.kreslavskiy@ki.se
|
| Phone |
+46761124813
|
| Organization name |
Karolinska Institutet
|
| Department |
Department of Medicine, Solna (MedS)
|
| Lab |
Taras Kreslavsky
|
| Street address |
Nks Bioclinicum, J7:30, Visionsgatan 4
|
| City |
Solna |
| ZIP/Postal code |
171 64 |
| Country |
Sweden |
| |
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| Platforms (2) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (18)
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| GSM3983810 |
58636: RNA-seq WT Alveolar macrophages #1 |
| GSM3983811 |
58637: RNA-seq WT Alveolar macrophages #2 |
| GSM3983812 |
58638: RNA-seq DKO Alveolar macrophages #1 |
| GSM3983813 |
58639: RNA-seq DKO Alveolar macrophages #2 |
| GSM3983814 |
64305: RNA-seq WT Alveolar macrophages - mixed bone marrow chimeras #1 |
| GSM3983815 |
64306: RNA-seq WT Alveolar macrophages - mixed bone marrow chimeras #2 |
| GSM3983816 |
64307: RNA-seq DKO Alveolar macrophages - mixed bone marrow chimeras #1 |
| GSM3983817 |
64308: RNA-seq DKO Alveolar macrophages - mixed bone marrow chimeras #2 |
| GSM3983818 |
82648: RNA-seq WT Peritoneal macrophages #1 |
| GSM3983819 |
82649: RNA-seq WT Peritoneal macrophages #2 |
| GSM3983820 |
82650: RNA-seq DKO Peritoneal macrophages #1 |
| GSM3983821 |
82651: RNA-seq DKO Peritoneal macrophages #2 |
| GSM3983822 |
70137: ChIP-seq Bhlhe40 WT Alveolar macrophages |
| GSM3983823 |
70136: Control track for Bhlhe40 ChIP-seq (mock’ precipitation sample without antibody) |
| GSM3983824 |
H3K27acWT1: ChIP-seq H3K27ac WT Alveolar macrophages #1 |
| GSM3983825 |
H3K27acWT2: ChIP-seq H3K27ac WT Alveolar macrophages #2 |
| GSM3983826 |
H3K27acDKO1: ChIP-seq H3K27ac DKO Alveolar macrophages #1 |
| GSM3983827 |
H3K27acDKO2: ChIP-seq H3K27ac DKO Alveolar macrophages #2 |
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| Relations |
| BioProject |
PRJNA557178 |
| SRA |
SRP216680 |
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