Hypoxic stress dysregulates functions of glioma-associated myeloid cells through epigenomic and transcriptional programs DOI Creative Commons
Monika Dźwigońska, Patrycja Rosa, Beata Kaza

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 16, 2024

ABSTRACT Hypoxia rapidly alters gene expression to allow cellular adaptation challenging conditions and support tumour growth. also affects the chromatin structure by modifications of histones DNA methylation. Glioblastoma (GBM) is an aggressive, deadly primary brain for which there no effective treatment. The microenvironment GBM highly heterogeneous, with infiltration glioma-associated microglia macrophages (GAMs) presence necrotic, hypoxic regions. mechanisms through hypoxia regulates functions infiltrating immune cells remain poorly understood. Here, we show that modulates myeloid markers in distinct ways: upregulates monocytic marker Lgals3 downregulates microglial P2ry12 Tmem119 GAMs vitro vivo , as shown using human mouse single-cell transcriptomics datasets. genome-wide hypoxia-dependent transcriptomic changes were determined microglia-glioma co-cultures. Numerous GAM subtype dysregulated response stress due associated accessibility, ATACseq. While alone drives a decrease overall accessibility at promoters, exposure glioma under leads both increases decreases promoter regions cells. enriched motifs transcription factors regarded master regulators cell identity function, including SPI1 or IRF8 . Overall, our data highlights importance strong intratumoral regulator functions, adds complexity characterisation particular subpopulations.

Language: Английский

CHTOP Promotes Microglia-Mediated Inflammation by Regulating Cell Metabolism and Inflammatory Gene Expression DOI
X. Edward Zhou,

Mengfei Lv,

Zhongying Duan

et al.

The Journal of Immunology, Journal Year: 2023, Volume and Issue: 212(4), P. 677 - 688

Published: Dec. 20, 2023

During the initiation of inflammatory response microglia, expression many inflammation- and cell metabolism-related genes alters. However, how transcription are coordinately regulated during inflammation is poorly understood. In this study, we found that LPS stimulation induced chromatin target PRMT1 (protein arginine methyltransferase 1) (CHTOP) in microglia. Knocking down CHTOP microglia decreased proinflammatory cytokine expression. addition, knockdown altered metabolism, as both upregulated were enriched pathways metabolites profile was greatly based on untargeted metabolomics analysis. Mechanistically, could directly bind regulatory elements to regulate their transcription. knocking increased neuronal viability vitro alleviated microglia-mediated neuroinflammation a systemic treatment mouse model. Collectively, these data revealed novel regulator promote by regulating genes.

Language: Английский

Citations

1
Hypoxic stress dysregulates functions of glioma-associated myeloid cells through epigenomic and transcriptional programs DOI Creative Commons
Monika Dźwigońska, Patrycja Rosa, Beata Kaza

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 16, 2024

ABSTRACT Hypoxia rapidly alters gene expression to allow cellular adaptation challenging conditions and support tumour growth. also affects the chromatin structure by modifications of histones DNA methylation. Glioblastoma (GBM) is an aggressive, deadly primary brain for which there no effective treatment. The microenvironment GBM highly heterogeneous, with infiltration glioma-associated microglia macrophages (GAMs) presence necrotic, hypoxic regions. mechanisms through hypoxia regulates functions infiltrating immune cells remain poorly understood. Here, we show that modulates myeloid markers in distinct ways: upregulates monocytic marker Lgals3 downregulates microglial P2ry12 Tmem119 GAMs vitro vivo , as shown using human mouse single-cell transcriptomics datasets. genome-wide hypoxia-dependent transcriptomic changes were determined microglia-glioma co-cultures. Numerous GAM subtype dysregulated response stress due associated accessibility, ATACseq. While alone drives a decrease overall accessibility at promoters, exposure glioma under leads both increases decreases promoter regions cells. enriched motifs transcription factors regarded master regulators cell identity function, including SPI1 or IRF8 . Overall, our data highlights importance strong intratumoral regulator functions, adds complexity characterisation particular subpopulations.

Language: Английский

Citations

0