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Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to PGE2 (ATAC-seq)

ABSTRACT: Metabolic engagement is intrinsic to immune cell function. Prostaglandin E2 (PGE2) has been shown to modulate macrophage activation, yet how PGE2 might affect metabolism is unclear. Here we show that PGE2 causes mitochondrial membrane potential (Δψm) to dissipate in interleukin-4 activated macrophages (M(IL-4)). Effects on Δψm are a consequence of PGE2-initiated transcriptional regulation of genes in the malate-aspartate shuttle (MAS), particularly GOT1. Reduced Δψm causes alterations in the expression of 126 voltage regulated genes (VRGs) including Resistin like molecule-α (RELMα), a key marker of M(IL-4), and genes that regulate cell cycle. The transcription factor ETS variant 1 (ETV1) plays a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a Δψm-sensitive transcription factor, and Δψm as a mediator of mitochondrial-directed nuclear gene expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE119463 | GEO | 2019/01/16

REPOSITORIES: GEO

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Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to PGE2

Project description:Metabolic engagement is intrinsic to immune cell function. Prostaglandin E2 (PGE2) has been shown to modulate macrophage activation, yet how PGE2 might affect metabolism is unclear. Here we show that PGE2 causes mitochondrial membrane potential (Δψm) to dissipate in interleukin-4 activated macrophages (M(IL-4)). Effects on Δψm are a consequence of PGE2-initiated transcriptional regulation of genes in the malate-aspartate shuttle (MAS), particularly GOT1. Reduced Δψm causes alterations in the expression of 126 voltage regulated genes (VRGs) including Resistin like molecule-α (RELMα), a key marker of M(IL-4), and genes that regulate cell cycle, The transcription factor ETS variant 1 (ETV1) plays a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a Δψm-sensitive transcription factor, and Δψm as a mediator of mitochondrial-directed nuclear gene expression.

2021-09-08 | PXD010997 | Pride

Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to PGE2 (RNA-seq)

Project description:Metabolic engagement is intrinsic to immune cell function. Prostaglandin E2 (PGE2) has been shown to modulate macrophage activation, yet how PGE2 might affect metabolism is unclear. Here we show that PGE2 causes mitochondrial membrane potential (Δψm) to dissipate in interleukin-4 activated macrophages (M(IL-4)). Effects on Δψm are a consequence of PGE2-initiated transcriptional regulation of genes in the malate-aspartate shuttle (MAS), particularly GOT1. Reduced Δψm causes alterations in the expression of 126 voltage regulated genes (VRGs) including Resistin like molecule-α (RELMα), a key marker of M(IL-4), and genes that regulate cell cycle. The transcription factor ETS variant 1 (ETV1) plays a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a Δψm-sensitive transcription factor, and Δψm as a mediator of mitochondrial-directed nuclear gene expression.

2019-01-16 | GSE119509 | GEO

Resistin-like molecule α provides vitamin A-dependent antimicrobial protection of the skin

Project description:The skin is the human body’s largest organ and is in contact with a diverse community of microorganisms that includes both resident and pathogenic bacteria. Skin immune defenses include the production of antimicrobial proteins that kill bacteria directly. However, we still have an incomplete understanding of how skin antimicrobial proteins promote homeostasis with resident bacterial communities and limit infection. Here, we show that resistin-like molecule α (RELMα) is an antibacterial protein that is produced by keratinocytes and sebocytes in the mouse skin. RELMα expression was induced in mouse skin by resident and pathogenic skin bacteria and was bactericidal for several bacterial species found on the skin, including Streptococcus pyogenes. Mice lacking RELMα had altered resident skin bacterial communities and were more susceptible to bacterial infection, indicating that RELMα controls bacterial colonization of the skin. RELMα expression required dietary vitamin A and could be induced by therapeutic retinoids that protected against bacterial infection in a RELMα-dependent manner. Resistin, another member of the RELM family, was expressed in human skin, required retinoids for expression, and killed skin bacteria, indicating a conserved function for RELM proteins in skin innate immunity. Our findings thus identify members of the RELM family as antibacterial proteins that provide vitamin A-dependent antimicrobial protection of the skin, and provide insight into why skin immunity requires adequate dietary vitamin A.

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2016-10-03 | GSE79031 | GEO

Macrophage-regulatory T cell interactions promote type 2 immune homeostasis through Resistin-like molecule α

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Project description:Cancers have unique metabolic adaptations in response to cell-intrinsic and environmental stressors, where identifying new strategies to target these adaptions is an area of active research. We previously described a dependency on a cytosolic aspartate aminotransaminase (GOT1)-dependent pathway for NADPH generation in pancreatic cancer. Here, we sought to identify metabolic dependencies following GOT1 inhibition to provide insight into the regulation of redox metabolism. Using pharmacological methods, we identified cysteine, glutathione, and lipid antioxidant function as metabolic vulnerabilities following GOT1 withdrawal. Targeting any of these pathways triggered ferroptosis, an oxidative, non-apoptotic, iron-dependent form of cell death in GOT1 knockdown cells. Mechanistically, GOT1 inhibition promoted a catabolic state and enhanced the availability of labile iron through autophagy and iron uptake. In sum, our study identifies a novel biochemical connection between GOT1, iron regulation, and ferroptosis, and suggests GOT1 plays a role in protecting PDA from metabolic stress.

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