The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin 300070, China.
Tianjin Key Laboratory of Digestive Diseases, Department of Gastroenterology and Hepatology, Medical University General Hospital, Tianjin Medical University, Tianjin 300070, China.
Nucleic Acids Res. 2024 Sep 23;52(17):10029-10039. doi: 10.1093/nar/gkae504.
Histone modifications are typically recognized by chromatin-binding protein modules (referred to as 'readers') to mediate fundamental processes such as transcription. Lysine β-hydroxybutyrylation (Kbhb) is a new type of histone mark that couples metabolism to gene expression. However, the readers that prefer histone Kbhb remain elusive. This knowledge gap should be filled in order to reveal the molecular mechanism of this epigenetic regulation. Herein, we developed a chemical proteomic approach, relying upon multivalent photoaffinity probes to capture binders of the mark, and identified ENL as a novel target of H3K9bhb. Biochemical studies and CUT&Tag analysis further suggested that ENL favorably binds to H3K9bhb, and co-localizes with it on promoter regions to modulate gene expression. Notably, disrupting the interaction between H3K9bhb and ENL via structure-based mutation led to the suppressed expression of genes such MYC that drive cell proliferation. Together, our work offered a chemoproteomics approach and identified ENL as a novel histone β-hydroxybutyrylation effector that regulates gene transcription, providing new insight into the regulation mechanism and function of histone Kbhb.
组蛋白修饰通常被染色质结合蛋白模块（称为“读取器”）识别，以介导转录等基本过程。赖氨酸β-羟丁酰化（Kbhb）是一种将代谢与基因表达偶联的新型组蛋白标记。然而，偏好组蛋白 Kbhb 的读取器仍然难以捉摸。为了揭示这种表观遗传调控的分子机制，应该填补这一知识空白。在此，我们开发了一种化学蛋白质组学方法，依赖于多价光亲和探针来捕获标记的结合物，并鉴定 ENL 为 H3K9bhb 的新型靶标。生化研究和 CUT&Tag 分析进一步表明，ENL 有利于与 H3K9bhb 结合，并与它在启动子区域共定位以调节基因表达。值得注意的是，通过基于结构的突变破坏 H3K9bhb 和 ENL 之间的相互作用，导致驱动细胞增殖的 MYC 等基因的表达受到抑制。总之，我们的工作提供了一种化学蛋白质组学方法，并鉴定了 ENL 作为一种新型的组蛋白β-羟丁酰化效应物，调节基因转录，为组蛋白 Kbhb 的调控机制和功能提供了新的见解。
