Mitochondrial fatty acid oxidation regulates monocytic type I interferon signaling via histone acetylation

• Published in: Science advances Vol. 11; no. 4; p. eadq9301
• Main Authors: Wu, Jing, Singh, Komudi, Shing, Vivian, Gupta, Anand, Arenberg, Brett C., Huffstutler, Rebecca D., Lee, Duck-Yeon, Sack, Michael N.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 24.01.2025
• Subjects: Acetyl Coenzyme A - metabolism; Acetyl-CoA C-Acetyltransferase - genetics; Acetyl-CoA C-Acetyltransferase - metabolism; Acetylation; Animals; Biochemistry; Biomedicine and Life Sciences; Fatty Acids - metabolism; Histones - metabolism; Humans; Immunology; Interferon Type I - metabolism; Macrophages - metabolism; Mice; Mitochondria - metabolism; Monocytes - metabolism; Oxidation-Reduction; SciAdv r-articles; Signal Transduction; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adq9301

Although lipid-derived acetyl–coenzyme A (CoA) is a major carbon source for histone acetylation, the contribution of fatty acid β-oxidation (FAO) to this process remains poorly characterized. To investigate this, we generated mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1, distal FAO enzyme) knockout macrophages. 13 C-carbon tracing confirmed reduced FA-derived carbon incorporation into histone H3, and RNA sequencing identified diminished interferon-stimulated gene expression in the absence of ACAT1. Chromatin accessibility at the Stat1 locus was diminished in ACAT1 −/− cells. Chromatin immunoprecipitation analysis demonstrated reduced acetyl-H3 binding to Stat1 promoter/enhancer regions, and increasing histone acetylation rescued Stat1 expression. Interferon-β release was blunted in ACAT1 −/− and recovered by ACAT1 reconstitution. Furthermore, ACAT1-dependent histone acetylation required an intact acetylcarnitine shuttle. Last, obese subjects’ monocytes exhibited increased ACAT1 and histone acetylation levels. Thus, our study identifies an intriguing link between FAO-mediated epigenetic control of type I interferon signaling and uncovers a potential mechanistic nexus between obesity and type I interferon signaling. Mitochondrial fatty acid oxidation is essential for the epigenetic control of type I interferon signaling.