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| Status |
Public on Jun 13, 2024 |
| Title |
Hypoxia drives HIF2-dependent reversible macrophagecellcycle entry |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Macrophages play critical roles across health and disease. Low oxygen conditions (hypoxia) have been associated primarily with cell cycle arrest in dividing cells. Macrophages are typically quiescent in G0, though yolk sac and bone marrow derived macrophages frequently proliferate and monocyte-derived tissue macrophages are able to proliferate in response to tissue signals. Here we show that hypoxia (1% oxygen tension) results in reversible entry into the cell cycle in human monocyte derived macrophages (MDM) and mouse peritoneal macrophages. Cell cycle progression is largely limited to G1/S phase with little progression to G2/M. Mechanistically, this cell cycle transitioning is triggered by a HIF2A-directed transcriptional program. The response is accompanied by increased expression of cell cycle-associated proteins, including CDK1, and reversible activation of the canonical mitogen-activated MEK-ERK proliferation pathway. CDK1 associated SAMHD1 phosphorylation at T592 in hypoxic macrophages renders them hyper-susceptible to lentiviral transduction. Furthermore, PHD inhibitors, which activate HIFs, are able to recapitulate HIF2A-dependent cell cycle entry in macrophages, as well as susceptibility to lentiviral transduction. Finally, we demonstrate that tumour associated macrophages (TAM) in lung cancers exhibit transcriptomic profiles representing responses to low oxygen and cell cycle progression at single cell level. This work uncovers HIF2A driven macrophage cell cycle progression in low oxygen conditions that culminates in SAMHD1 phosphorylation and high susceptibility to lentiviral transduction. These findings have additional implications for inflammation and tumour progression/metastasis where low oxygen environments are common.
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| Overall design |
To investigate the transcriptional responses of macrophages in response to hypoxia, we generated RNA-Seq data sets from normoxic and hypoxic conditions.
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| Contributor(s) |
Meng B, Wit N, Nathan J, Gupta RK |
| Citation missing |
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| Submission date |
Jun 12, 2024 |
| Last update date |
Jun 14, 2024 |
| Contact name |
Niek Wit |
| E-mail(s) |
nw416@cam.ac.uk
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| Organization name |
University of Cambridge
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| Department |
Department of Medicine
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| Lab |
Professor James Nathan
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| Street address |
Puddicombe Way
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| City |
Cambridge |
| State/province |
Not US or Canada |
| ZIP/Postal code |
CB2 0AW |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA1123255 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE269699_RAW.tar |
39.2 Mb |
(http)(custom) |
TAR (of SF) |
SRA Run Selector |
| Raw data are available in SRA |
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