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Palmitic acid alters enhancers and super-enhancers near inflammatory and efferocytosis-associated genes in human monocytes

ABSTRACT: Free fatty acids like palmitic acid (PA) are elevated in obesity and diabetes and dysregulate monocyte and macrophage functions, contributing to enhanced inflammation in these cardiometabolic diseases. Epigenetic mechanisms regulating enhancer functions play key roles in inflammatory gene expression, but their role in PA-induced monocyte/macrophage dysfunction is unknown. We found that PA treatment altered the epigenetic landscape of enhancers and super-enhancers (SEs) in human monocytes. Integration with RNA-seq data revealed that PA-induced enhancers/SEs correlated with PA-increased expression of inflammatory and immune response genes, while PA-inhibited enhancers correlated with downregulation of phagocytosis and efferocytosis genes. These genes were similarly regulated in macrophages from mouse models of diabetes and accelerated atherosclerosis, human atherosclerosis, and by infectious agents. PA-regulated enhancers/SEs harbored SNPs associated with diabetes, obesity, and body mass index indicating disease relevance. We verified increased chromatin interactions between PA-regulated enhancers/SEs and inflammatory gene promoters, and reduced interactions at efferocytosis genes. PA-induced gene expression was reduced by inhibitors of BRD4, and NF-kB. PA treatment inhibited phagocytosis and efferocytosis in human macrophages. Together, our results show that PA-induced enhancer dynamics at key monocyte/macrophage enhancers/SEs regulate inflammatory and immune genes and responses. Targeting these PA-regulated epigenetic changes could provide novel therapeutic opportunities for cardiometabolic disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281939 | GEO | 2025/04/23

REPOSITORIES: GEO

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Project description:BACKGROUND: Obesity and diabetes are associated with elevated free fatty acids like palmitic acid (PA), which promote chronic inflammation and impaired inflammation resolution associated with cardiometabolic disorders. Long non-coding RNAs (lncRNAs) are implicated in inflammatory processes, however, their roles in PA-regulated inflammation and resolution are unclear. METHODS: We performed RNA-seq analysis to identify PA-regulated coding genes and novel lncRNAs in CD14+ monocytes from healthy volunteers. We investigated the regulation and function of an uncharacterized PA-induced lncRNA PARAIL (PA-regulated anti-inflammatory lncRNA). We examined its role in inflammation resolution employing knockdown and overexpression strategies in human and mouse macrophages. We also used RNA-pulldown coupled to mass spectrometry to identify PARAIL interacting nuclear proteins and their mechanistic involvement in PARAIL functions in human macrophages. RESULTS: Treatment of human CD14+ monocytes with PA induced several lncRNAs and genes associated with inflammatory phenotype. PA strongly induced lncRNA PARAIL expressed near RIPK2. PARAIL was also induced by cytokines and infectious agents in human monocytes/macrophages and was regulated by NF-kB. Time course studies showed PARAIL was induced during inflammation resolution phase in PA treated macrophages. Knockdown of PARAIL with antisense oligonucleotides upregulated key inflammatory genes and vice versa with PARAIL overexpression. We found that PARAIL interacts with Human Antigen R (HuR) protein via AU-rich elements (AREs). HuR knockdown inhibited the anti-inflammatory functions of PARAIL. Moreover, PARAIL knockdown increased cytosolic localization of HuR and increased the stability of ARE-containing inflammatory mRNAs. Mouse orthologous Parail was downregulated in macrophages from mice with diabetes and atherosclerosis. Parail overexpression attenuated pro-inflammatory genes in mouse macrophages. CONCLUSIONS: Upregulation of PARAIL under acute inflammatory conditions contributes to pro-resolution mechanisms via PARAIL-HuR interactions. Conversely, PARAIL downregulation in cardiometabolic diseases enhances HuR function and impairs inflammation resolution to further augment inflammation. Thus, inflammation-resolving lncRNAs like PARAIL represent novel tools to combat inflammatory cardiometabolic diseases.

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Palmitic acid alters enhancers and super-enhancers near inflammatory and efferocytosis-associated genes in human monocytes

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