Wu Jing, Singh Komudi, Shing Vivian, Gupta Anand, Arenberg Brett C, Huffstutler Rebecca D, Lee Duck-Yeon, Sack Michael N
Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Sci Adv. 2025 Jan 24;11(4):eadq9301. doi: 10.1126/sciadv.adq9301. Epub 2025 Jan 22.
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. 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 locus was diminished in ACAT1 cells. Chromatin immunoprecipitation analysis demonstrated reduced acetyl-H3 binding to promoter/enhancer regions, and increasing histone acetylation rescued 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.
尽管脂质衍生的乙酰辅酶A（CoA）是组蛋白乙酰化的主要碳源，但脂肪酸β氧化（FAO）对这一过程的贡献仍未得到充分表征。为了对此进行研究，我们构建了线粒体乙酰辅酶A乙酰转移酶1（ACAT1，FAO远端酶）基因敲除的巨噬细胞。碳追踪证实FA衍生的碳掺入组蛋白H3减少，RNA测序确定在缺乏ACAT1的情况下干扰素刺激基因的表达减少。ACAT1基因敲除细胞中该基因座的染色质可及性降低。染色质免疫沉淀分析表明，乙酰化H3与该基因启动子/增强子区域的结合减少，增加组蛋白乙酰化可挽救该基因的表达。ACAT1基因敲除细胞中干扰素-β释放减弱，ACAT1基因重构后恢复。此外，ACAT1依赖的组蛋白乙酰化需要完整的乙酰肉碱穿梭系统。最后，肥胖受试者的单核细胞表现出ACAT1和组蛋白乙酰化水平升高。因此，我们的研究确定了FAO介导的I型干扰素信号表观遗传调控之间的有趣联系，并揭示了肥胖与I型干扰素信号之间潜在的机制联系。
