Benevolenskaya, E. V. | bioRxiv Science

bioRxiv2024

Metabolic shift to serine pathway induced by lipids confers oncogenic properties in non-transformed breast cells

A lipid metabolism gene signature is associated with the risk of estrogen negative breast cancer (ER-BC). In vitro, lipid exposure alters histone methylation affecting gene expression and increasing flux through various metabolic reactions; but little is known about the mechanism(s) linking lipids and epigenetic reprogramming with the genesis of ER-BC. Here we show that the metabolism of the medium-chain fatty acid Octanoic Acid (OA) in preference to glucose and glutamine results in a metabolic shift toward the serine pathway increasing the production of SAM, glutathione, and 2-HG, with implications for oncogenesis: SAM production results in epigenetic fostered plasticity leading to reprogramming/selecting cells that express Neural, EMT and BC related genes. 2-HG exposure results in appearance of DNA breaks, potentially consequent to the inhibition of essential demethylases for HR repair. ROS increases shortly after OA exposure and is mitigated by antioxidant defenses, which favors/enables the survival of specific cell subtypes.

cancer biology↗

bioRxiv2023

Diet-induced obesity dysregulates chromatin oxygen sensing regulating efferocytosis in macrophages

Macrophages are plastic cell populations that normally adapt to their environment. Cellular adaptation to hypoxia occurs through transcription factors including hypoxia-inducible factors, and hypoxia-inducible transcriptions are further regulated by chromatin response through histone modification including histone methylation. However, the role of histone methylation in the hypoxia response of macrophages is not well understood. As obesity is associated with dysregulated macrophage functions, we investigated whether hypoxia response is cell-intrinsically dysregulated in macrophages in obesity. In mouse bone marrow-derived macrophages (BMDMs), immunoblotting revealed that 1% hypoxia rapidly increases the global levels of histone 3 methylations. We found that hypoxia-induction of histone 3-lysine 4 tri-methylation (H3K4me3) is specifically inhibited in BMDMs from mice fed a high-fat diet (HFD-BMDMs) compared to BMDMs from mice fed a normal diet (ND-BMDMs). Multi-omics approach with ChIP-seq and RNA-seq identified that glycolysis-related pathways and genes including Aldoa are upregulated after prolonged hypoxia along with upregulated H3K4me3 in ND-BMDMs. In contrast, no pathway is associated with hypoxia-upregulated H3K4me3 peaks in HFD-BMDMs and hypoxia-induced Aldoa expression is decreased in HFD-BMDMs, suggesting both the extent and the genome location of H3K4me3 response to hypoxia is dysregulated in obesity. Consistently, lactate accumulation and induction of histone lactylation under hypoxia are reduced in HFD-BMDMs. Furthermore, HFD-BMDMs exhibited decreased dying cell clearance under hypoxia due to the reduced capacity of anaerobic glycolysis. Competitive bone marrow transplantation of hematopoietic stem cells (HSCs) shows that HFD-induced long-term memory reflects the impaired dying cell clearance in differentiated BMDMs, which is rescued by inhibiting oxidative stress in HSCs. In summary, chromatin response to hypoxia associated with H3K4me3 enrichment governs transcriptions for anaerobic glycolysis and dying cell clearance under hypoxia. Obesity dysregulates the extent and the genome location of H3K4me3 enrichment, glycolysis, and dying cell clearance of BMDMs under hypoxia, which is initiated in HSPCs via oxidative stress.

cell biology↗