组蛋白乳酰化促进心肌梗死后修复性基因的激活。
Histone Lactylation Boosts Reparative Gene Activation Post-Myocardial Infarction.
机构信息
Department of Cardiology (N.W., W.W., X.W., G.M., X.Y., Z.T., Q.Y., M.W., L.C., J. Cui, M.Y., Y.Z., D.W., J.W., M.Z., B.Y.), the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China (N.W., W.W., X.W., G.M., X.Y., Z.T., Q.Y., M.W., L.C., P.S., J. Cui, M.Y., Y.Z., D.W., J.W., M.Z., B.Y.).
出版信息
Circ Res. 2022 Nov 11;131(11):893-908. doi: 10.1161/CIRCRESAHA.122.320488. Epub 2022 Oct 21.
BACKGROUND
Inflammation resolution and cardiac repair initiation after myocardial infarction (MI) require timely activation of reparative signals. Histone lactylation confers macrophage homeostatic gene expression signatures via transcriptional regulation. However, the role of histone lactylation in the repair response post-MI remains unclear. We aimed to investigate whether histone lactylation induces reparative gene expression in monocytes early and remotely post-MI.
METHODS
Single-cell transcriptome data indicated that reparative genes were activated early and remotely in bone marrow and circulating monocytes before cardiac recruitment. Western blotting and immunofluorescence staining revealed increases in histone lactylation levels, including the previously identified histone H3K18 lactylation in monocyte-macrophages early post-MI. Through joint CUT&Tag and RNA-sequencing analyses, we identified , and as histone H3K18 lactylation target genes. The increased modification and expression levels of these target genes post-MI were verified by chromatin immunoprecipitation-qPCR and reverse transcription-qPCR.
RESULTS
We demonstrated that histone lactylation regulates the anti-inflammatory and pro-angiogenic dual activities of monocyte-macrophages by facilitating reparative gene transcription and confirmed that histone lactylation favors a reparative environment and improves cardiac function post-MI. Furthermore, we explored the potential positive role of monocyte histone lactylation in reperfused MI. Mechanistically, we provided new evidence that monocytes undergo metabolic reprogramming in the early stage of MI and demonstrated that dysregulated glycolysis and MCT1 (monocarboxylate transporter 1)-mediated lactate transport promote histone lactylation. Finally, we revealed the catalytic effect of IL (interleukin)-1β-dependent GCN5 (general control non-depressible 5) recruitment on histone H3K18 lactylation and elucidated its potential role as an upstream regulatory element in the regulation of monocyte histone lactylation and downstream reparative gene expression post-MI.
CONCLUSIONS
Histone lactylation promotes early remote activation of the reparative transcriptional response in monocytes, which is essential for the establishment of immune homeostasis and timely activation of the cardiac repair process post-MI.
背景
心肌梗死（MI）后炎症消退和心脏修复启动需要及时激活修复信号。组蛋白乳酰化通过转录调控赋予巨噬细胞稳态基因表达特征。然而，组蛋白乳酰化在 MI 后修复反应中的作用尚不清楚。我们旨在研究组蛋白乳酰化是否在 MI 后早期和远程诱导单核细胞中的修复基因表达。
方法
单细胞转录组数据表明，在心脏募集之前，骨髓和循环单核细胞中早期和远程激活了修复基因。Western blot 和免疫荧光染色显示，MI 后早期单核细胞-巨噬细胞中组蛋白乳酰化水平升高，包括先前鉴定的组蛋白 H3K18 乳酰化。通过联合 CUT&Tag 和 RNA-seq 分析，我们鉴定出 和 作为组蛋白 H3K18 乳酰化的靶基因。通过染色质免疫沉淀-qPCR 和逆转录-qPCR 验证了这些靶基因在 MI 后修饰和表达水平的增加。
结果
我们证明组蛋白乳酰化通过促进修复基因转录来调节单核细胞-巨噬细胞的抗炎和促血管生成双重活性，并证实组蛋白乳酰化有利于 MI 后修复环境和改善心脏功能。此外，我们探索了单核细胞组蛋白乳酰化在再灌注 MI 中的潜在积极作用。在机制上，我们提供了新的证据表明，单核细胞在 MI 的早期阶段经历代谢重编程，并证明失调的糖酵解和 MCT1（单羧酸转运蛋白 1）介导的乳酸转运促进组蛋白乳酰化。最后，我们揭示了 IL（白细胞介素）-1β依赖性 GCN5（一般控制非抑制 5）募集对组蛋白 H3K18 乳酰化的催化作用，并阐明了其作为 MI 后单核细胞组蛋白乳酰化和下游修复基因表达调控的上游调节元件的潜在作用。
结论
组蛋白乳酰化促进单核细胞中修复转录反应的早期远程激活，这对于 MI 后免疫稳态的建立和心脏修复过程的及时激活至关重要。
Zotero 插件