Département d'anatomie et biologie cellulaire, Faculté de médecine et des sciences de la santé, Pavillon de recherche appliquée sur le cancer, Université de Sherbrooke, Sherbrooke, Québec, J1E 4K8, Canada.
Sci Rep. 2019 Mar 29;9(1):5363. doi: 10.1038/s41598-019-41842-6.
Both HDAC1 and HDAC2 are class I deacetylases acting as erasers of lysine-acetyl marks on histones and non-histone proteins. Several histone deacetylase inhibitors, either endogenous to the cell, such as the ketogenic β-hydroxybutyrate metabolite, or exogenous, such as butyrate, a microbial-derived metabolite, regulate HDAC activity. Different combinations of intestinal epithelial cell (IEC)-specific Hdac1 and/or Hdac2 deletion differentially alter mucosal homeostasis in mice. Thus, HDAC1 and HDAC2 could act as sensors and transmitters of environmental signals to the mucosa. In this study, enteroid culture models deleted for Hdac1 or Hdac2 were established to determine IEC-specific function as assessed by global transcriptomic and proteomic approaches. Results show that Hdac1 or Hdac2 deficiency altered differentiation of Paneth and goblet secretory cells, which sustain physical and chemical protection barriers, and increased intermediate secretory cell precursor numbers. Furthermore, IEC Hdac1- and Hdac2-dependent common and specific biological processes were identified, including oxidation-reduction, inflammatory responses, and lipid-related metabolic processes, as well as canonical pathways and upstream regulators related to environment-dependent signaling through steroid receptor pathways, among others. These findings uncover unrecognized regulatory similarities and differences between Hdac1 and Hdac2 in IEC, and demonstrate how HDAC1 and HDAC2 may complement each other to regulate the intrinsic IEC phenotype.
HDAC1 和 HDAC2 均为 I 类去乙酰化酶，可作为组蛋白和非组蛋白上赖氨酸乙酰化标记的“橡皮擦”。几种组蛋白去乙酰化酶抑制剂，无论是细胞内源性的，如酮体 β-羟丁酸代谢物，还是外源性的，如丁酸，一种微生物衍生的代谢物，均可调节 HDAC 活性。肠上皮细胞 (IEC) 特异性 Hdac1 和/或 Hdac2 缺失的不同组合可在小鼠中不同程度地改变黏膜稳态。因此，HDAC1 和 HDAC2 可以作为环境信号向黏膜传递的传感器和递质。在这项研究中，建立了缺失 Hdac1 或 Hdac2 的肠类器官培养模型，以通过全局转录组学和蛋白质组学方法确定 IEC 特异性功能。结果表明，Hdac1 或 Hdac2 缺失改变了潘氏细胞和杯状分泌细胞的分化，这些细胞维持着物理和化学保护屏障，并增加了中间分泌细胞前体的数量。此外，还鉴定了 IEC Hdac1 和 Hdac2 依赖性的共同和特定生物学过程，包括氧化还原、炎症反应和与脂质相关的代谢过程，以及与类固醇受体途径相关的环境依赖信号传导的经典途径和上游调节剂等。这些发现揭示了 IEC 中 HDAC1 和 HDAC2 之间未被识别的调节相似性和差异性，并证明了 HDAC1 和 HDAC2 如何相互补充以调节内在的 IEC 表型。
