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, Canada.
Am J Physiol Gastrointest Liver Physiol. 2014 Apr 1;306(7):G594-605. doi: 10.1152/ajpgi.00393.2013. Epub 2014 Feb 13.
Histone deacetylases (Hdac) remove acetyl groups from proteins, influencing global and specific gene expression. Hdacs control inflammation, as shown by Hdac inhibitor-dependent protection from dextran sulfate sodium (DSS)-induced murine colitis. Although tissue-specific Hdac knockouts show redundant and specific functions, little is known of their intestinal epithelial cell (IEC) role. We have shown previously that dual Hdac1/Hdac2 IEC-specific loss disrupts cell proliferation and determination, with decreased secretory cell numbers and altered barrier function. We thus investigated how compound Hdac1/Hdac2 or Hdac2 IEC-specific deficiency alters the inflammatory response. Floxed Hdac1 and Hdac2 and villin-Cre mice were interbred. Compound Hdac1/Hdac2 IEC-deficient mice showed chronic basal inflammation, with increased basal disease activity index (DAI) and deregulated Reg gene colonic expression. DSS-treated dual Hdac1/Hdac2 IEC-deficient mice displayed increased DAI, histological score, intestinal permeability, and inflammatory gene expression. In contrast to double knockouts, Hdac2 IEC-specific loss did not affect IEC determination and growth, nor result in chronic inflammation. However, Hdac2 disruption protected against DSS colitis, as shown by decreased DAI, intestinal permeability and caspase-3 cleavage. Hdac2 IEC-specific deficient mice displayed increased expression of IEC gene subsets, such as colonic antimicrobial Reg3b and Reg3g mRNAs, and decreased expression of immune cell function-related genes. Our data show that Hdac1 and Hdac2 are essential IEC homeostasis regulators. IEC-specific Hdac1 and Hdac2 may act as epigenetic sensors and transmitters of environmental cues and regulate IEC-mediated mucosal homeostatic and inflammatory responses. Different levels of IEC Hdac activity may lead to positive or negative outcomes on intestinal homeostasis during inflammation.
组蛋白去乙酰化酶（Hdac）从蛋白质上去除乙酰基，影响全局和特定基因的表达。Hdac 控制炎症，这一点可以通过依赖 Hdac 抑制剂的葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎保护来证明。尽管组织特异性 Hdac 敲除显示出冗余和特定的功能，但它们在肠上皮细胞（IEC）中的作用知之甚少。我们之前已经表明，双重 Hdac1/Hdac2 IEC 特异性缺失会破坏细胞增殖和分化，导致分泌细胞数量减少和屏障功能改变。因此，我们研究了复合 Hdac1/Hdac2 或 Hdac2 IEC 特异性缺失如何改变炎症反应。Floxed Hdac1 和 Hdac2 以及微管蛋白-Cre 小鼠进行杂交。复合 Hdac1/Hdac2 IEC 缺陷小鼠表现出慢性基础炎症，基础疾病活动指数（DAI）升高，Reg 基因结肠表达失调。DSS 处理的双重 Hdac1/Hdac2 IEC 缺陷小鼠显示出更高的 DAI、组织学评分、肠通透性和炎症基因表达。与双敲除小鼠相反，Hdac2 IEC 特异性缺失不会影响 IEC 的决定和生长，也不会导致慢性炎症。然而，Hdac2 缺失可防止 DSS 结肠炎，表现为 DAI、肠通透性和半胱天冬酶-3 切割降低。Hdac2 IEC 特异性缺失的小鼠显示出 IEC 基因亚群的表达增加，例如结肠抗菌 Reg3b 和 Reg3g mRNA，以及免疫细胞功能相关基因的表达降低。我们的数据表明，Hdac1 和 Hdac2 是 IEC 稳态调节的必需因子。IEC 特异性 Hdac1 和 Hdac2 可能作为环境线索的表观遗传传感器和传递者发挥作用，调节 IEC 介导的粘膜稳态和炎症反应。不同水平的 IEC Hdac 活性可能会导致在炎症期间对肠道稳态产生积极或消极的影响。
