Department of Cellular Biology and Molecular Medicine, Rutgers University-New Jersey Medical School, Newark, NJ, 07103, USA.
Center for Translational Medicine, Temple University, Philadelphia, PA, 19140, USA.
Mol Metab. 2021 Nov;53:101249. doi: 10.1016/j.molmet.2021.101249. Epub 2021 May 11.
We previously reported that β-oxidation enzymes are present in the nucleus in close proximity to transcriptionally active promoters. Thus, we hypothesized that the fatty acid intermediate, butyryl-CoA, is the substrate for histone butyrylation and its abundance is regulated by acyl-CoA dehydrogenase short chain (ACADS). The objective of this study was to determine the genomic distribution of H3K9-butyryl (H3K9Bu) and its regulation by dietary fat, stress, and ACADS and its impact on gene expression.
Using genome-wide chromatin immunoprecipitation-sequencing (ChIP-Seq), we show that H3K9Bu is abundant at all transcriptionally active promoters, where, paradoxically, it is most enriched in mice fed a fat-free vs high-fat diet. Deletion of fatty acid synthetase (FASN) abolished H3K9Bu in cells maintained in a glucose-rich but not fatty acid-rich medium, signifying that fatty acid synthesis from carbohydrates substitutes for dietary fat as a source of butyryl-CoA. A high-fat diet induced an increase in ACADS expression that accompanied the decrease in H3K9Bu. Conversely, the deletion of ACADS increased H3K9Bu in human cells and mouse hearts and reversed high-fat- and stress-induced reduction in promoter-H3K9Bu, whose abundance coincided with diminished stress-regulated gene expression as revealed by RNA sequencing. In contrast, H3K9-acetyl (H3K9Ac) abundance was minimally impacted by diet.
Promoter H3K9 butyrylation is a major histone modification that is negatively regulated by high fat and stress in an ACADS-dependent fashion and moderates stress-regulated gene expression.
我们之前曾报道过，β-氧化酶存在于细胞核中，靠近转录活跃的启动子。因此，我们假设脂肪酸中间产物丁酰辅酶 A 是组蛋白丁酰化的底物，其丰度受酰基辅酶 A 脱氢酶短链（ACADS）调节。本研究的目的是确定 H3K9-丁酰基（H3K9Bu）的基因组分布及其受膳食脂肪、应激和 ACADS 的调节及其对基因表达的影响。
通过全基因组染色质免疫沉淀测序（ChIP-Seq），我们发现 H3K9Bu 在所有转录活跃的启动子上都很丰富，而在高脂肪饮食喂养的小鼠中，它在这些启动子上的丰度最高，这是矛盾的。脂肪酸合酶（FASN）的缺失消除了在富含葡萄糖而不是富含脂肪酸的培养基中培养的细胞中的 H3K9Bu，这表明从碳水化合物合成脂肪酸可以替代膳食脂肪作为丁酰辅酶 A 的来源。高脂肪饮食诱导 ACADS 表达增加，同时 H3K9Bu 减少。相反，ACADS 的缺失增加了人细胞和小鼠心脏中的 H3K9Bu，并逆转了高脂肪和应激诱导的启动子 H3K9Bu 减少，其丰度与 RNA 测序显示的应激调节基因表达减少一致。相比之下，H3K9-乙酰基（H3K9Ac）的丰度受饮食影响最小。
启动子 H3K9 丁酰化是一种主要的组蛋白修饰，受 ACADS 依赖的高脂肪和应激的负调节，并调节应激调节基因的表达。
