Macrophage inflammatory and regenerative response periodicity is programmed by cell cycle and chromatin state

Dániel, Bence; Meier, Stefanie; Chen, Andy Y.; Sandor, Katalin; Czimmerer, Zsolt; Varga, Zsofia; Bene, Krisztian; Buquicchio, Frank A.; Qi, Yanyan; Kitano, Hugo C.; Wheeler, Joshua; Foster, Deshka S.; Januszyk, Michael; Longaker, Michael T.; Chang, Howard Y.; Satpathy, Ansuman T.

doi:10.1016/j.molcel.2022.11.017

Cited by 17 publications

(14 citation statements)

References 65 publications

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“…This IFN expression heterogeneity is in line with the previous reports (Cai, Zhou et al 2017). To investigate how the host cell state might be affecting the IFN expression, we focused on the cell cycle phase, which has been previously implicated in immune-mediated responses (Genin, Cuvelier et al 2015, Bressy, Droby et al 2019, Daniel, Belk et al 2023). We grouped cells according to their cell cycle phases using gene expression differences that mark S and G2/M phases (Hao, Hao et al 2021).…”

Section: Resultsmentioning

confidence: 99%

G1/S Boundary Activates Interferon and Inflammatory Response Genes

Büyükkahraman,

Kim

2023

Preprint

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Interferons (IFNs) have various roles in antiviral immunity, including curbing the immune system to prevent tissue damage and stimulating adaptive immunity. Due to its protective and destructive properties, IFN expression is tightly regulated. In contrast to its tight regulatory control, IFN expression is highly heterogeneous across many cell types upon pathogenic stimulus. The basis for this heterogenous IFN expression remains incompletely understood. Using single cell RNA-sequencing upon viral infection, we found that interferon expression is upregulated specifically in the late G1 phase of the cell cycle, and cell synchronization at the G1/S boundary boosts interferon expression. Furthermore, cell cycle arrest without any additional stimulus is sufficient to upregulate interferons and hundreds of other inflammatory response genes. Interferon upregulation at the G1/S boundary is cell type specific and not observed in non-immune cell types. Finally, we use ATAC-seq to identify potential transcription factors orchestrating this response. Together, these results uncover the cell cycle as a critical regulator of IFN expression in immune cells.

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Section: Resultsmentioning

confidence: 99%

G1/S Boundary Activates Interferon and Inflammatory Response Genes

Büyükkahraman,

Kim

2023

Preprint

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“…Cell cycle regulation not only impacts the process of cell division but also inflammatory responses 37,38 . High dNTP levels are detrimental for cells, both due to increased likelihood of parasitisation by DNA viruses and other micro-organisms, and possibly higher rates of spontaneous mutation following DNA damage and repair.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia drives HIF2-dependent macrophage cell cycle entry and susceptibility to lentiviral transduction

Meng,

Zhao,

Mlcochova

et al. 2023

Preprint

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Macrophages play critical roles across health and disease. Low oxygen conditions (hypoxia) have been associated primarily with cell cycle arrest in cultured 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 monocyte derived macrophages (MDM) and mouse peritoneal macrophages. Cell cycle progression is largely limited to G1/S phase with very little progression to G2/M. Mechanistically, this cell cycle transitioning is triggered by a HIF2α-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 HIF2α-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 HIF2α driven macrophage cell cycle progression in low oxygen conditions that culminates in SAMHD1 phosphorylation and high susceptibility to lentiviral transduction. These findings have implications for inflammation, neoplasia and pathogen defence.

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“…These STAT6‐repressed enhancers are also characterized by diminished PU.1 and co‐activator P300 binding and decreased chromatin accessibility following short‐term IL‐4 exposure 56,57 . Intriguingly, it has recently been demonstrated that many direct IL‐4‐STAT6 target genes show distinct IL‐4 inducibility in different cell cycle phases of murine bone marrow‐derived macrophages, raising the possibility that the STAT6 binding or its transcriptional activator capacity is also regulated in a cell cycle‐dependent manner at different enhancer sets 58 …”

Section: Il‐4‐orchestrated Stat6 Egr2 and Pparγ Containing Tf Network...mentioning

confidence: 99%

“…We reported that the attenuated response of the selected genes, including Ccl5 , Irg1, and Irf8 , to IFNγ in the alternatively polarized macrophages proved quite progressive, resulting in almost complete desensitization after the fourth IL‐4 restimulation and thus IFNγ resistance 44 . It has been recently published that macrophage responsiveness to IFNγ markedly reduced in S and G2/M cell cycle phases, while IL‐4 induces the cell cycle phase distribution toward the G2/M phase resulting in the subpopulation‐specific reduced IFNγ responsiveness in the IL‐4 polarized macrophage populations 58 . Besides, we observed that the direct transcriptional repressor activity of the STAT6 transcription factor also affects the specific subset of the inflammatory enhancers attenuating both their basal activity and TLR their inducibility by TLR ligand LPS.…”

Section: Il‐4‐induced Tf Network Supports the Unique Responsiveness O...mentioning

confidence: 99%

Epigenomic regulation of macrophage polarization: Where do the nuclear receptors belong?

Czimmerer

Nagy

2023

Immunological Reviews

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SummaryOur laboratory has a long‐standing research interest in understanding how lipid‐activated transcription factors, nuclear hormone receptors, contribute to dendritic cell and macrophage gene expression regulation, subtype specification, and responses to a changing extra and intracellular milieu. This journey in the last more than two decades took us from identifying target genes for various RXR heterodimers to systematically mapping nuclear receptor‐mediated pathways in dendritic cells to identifying hierarchies of transcription factors in alternative polarization in macrophages to broaden the role of nuclear receptors beyond strictly ligand‐regulated gene expression. We detail here the milestones of the road traveled and draw conclusions regarding the unexpectedly broad role of nuclear hormone receptors as epigenomic components of dendritic cell and macrophage gene regulation as we are getting ready for the next challenges.

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Macrophage inflammatory and regenerative response periodicity is programmed by cell cycle and chromatin state

Cited by 17 publications

References 65 publications

G1/S Boundary Activates Interferon and Inflammatory Response Genes

G1/S Boundary Activates Interferon and Inflammatory Response Genes

Hypoxia drives HIF2-dependent macrophage cell cycle entry and susceptibility to lentiviral transduction

Epigenomic regulation of macrophage polarization: Where do the nuclear receptors belong?

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