Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cell Rep. 2021 Nov 23;37(8):110044. doi: 10.1016/j.celrep.2021.110044.
β-hydroxybutyrate (β-OHB) is an essential metabolic energy source during fasting and functions as a chromatin regulator by lysine β-hydroxybutyrylation (Kbhb) modification of the core histones H3 and H4. We report that Kbhb on histone H3 (H3K9bhb) is enriched at proximal promoters of critical gene subsets associated with lipolytic and ketogenic metabolic pathways in small intestine (SI) crypts during fasting. Similar Kbhb enrichment is observed in Lgr5 stem cell-enriched epithelial spheroids treated with β-OHB in vitro. Combinatorial chromatin state analysis reveals that H3K9bhb is associated with active chromatin states and that fasting enriches for an H3K9bhb-H3K27ac signature at active metabolic gene promoters and distal enhancer elements. Intestinal knockout of Hmgcs2 results in marked loss of H3K9bhb-associated loci, suggesting that local production of β-OHB is responsible for chromatin reprogramming within the SI crypt. We conclude that modulation of H3K9bhb in SI crypts is a key gene regulatory event in response to fasting.
β-羟基丁酸 (β-OHB) 是禁食期间的重要代谢能量来源，通过核心组蛋白 H3 和 H4 的赖氨酸 β-羟丁酸化 (Kbhb) 修饰作为染色质调节剂发挥作用。我们报告说，在禁食期间小肠 (SI) 隐窝中与脂肪分解和生酮代谢途径相关的关键基因亚群的近端启动子处富含组蛋白 H3 上的 Kbhb (H3K9bhb)。在体外用 β-OHB 处理富含 Lgr5 干细胞的上皮球体中也观察到类似的 Kbhb 富集。组合染色质状态分析表明，H3K9bhb 与活性染色质状态相关，并且禁食会使活跃代谢基因启动子和远端增强子元件上的 H3K9bhb-H3K27ac 特征富集。Hmgcs2 基因在肠道中的敲除导致与 H3K9bhb 相关的基因座明显丢失，这表明局部产生的 β-OHB 负责 SI 隐窝内的染色质重编程。我们得出结论，SI 隐窝中 H3K9bhb 的调节是对禁食反应的关键基因调控事件。
