We have previously reported that histone deacetylase epigenetic regulator Hdac1 and Hdac2 deletion in intestinal epithelial cells (IEC) disrupts mucosal tissue architecture and barrier, causing chronic inflammation. In this study, proteome and transcriptome analysis revealed the importance of signaling pathways induced upon genetic IEC-Hdac1 and Hdac2 deletion. Indeed, Gene Ontology biological process analysis of enriched deficient IEC RNA and proteins identified common pathways, including lipid metabolic and oxidation–reduction process, cell adhesion, and antigen processing and presentation, related to immune responses, correlating with dysregulation of major histocompatibility complex (MHC) class II genes. Top upstream regulators included regulators associated with environmental sensing pathways to xenobiotics, microbial and diet-derived ligands, and endogenous metabolites. Proteome analysis revealed mTOR signaling IEC-specific defects. In addition to mTOR, the STAT and Notch pathways were dysregulated specifically in jejunal IEC. To determine the impact of pathway dysregulation on mutant jejunum alterations, we treated mutant mice with Tofacitinib, a JAK inhibitor. Treatment with the inhibitor partially corrected proliferation and tight junction defects, as well as niche stabilization by increasing Paneth cell numbers. Thus, IEC-specific histone deacetylases 1 (HDAC1) and 2 (HDAC2) support intestinal homeostasis by regulating survival and translation processes, as well as differentiation and metabolic pathways. HDAC1 and HDAC2 may play an important role in the regulation of IEC-specific inflammatory responses by controlling, directly or indirectly, the JAK/STAT pathway. IEC-specific JAK/STAT pathway deregulation may be, at least in part, responsible for intestinal homeostasis disruption in mutant mice.

中文翻译：

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JAK-STAT 通路抑制部分恢复 Hdac1 和 Hdac2 肠道上皮细胞缺陷小鼠的肠道稳态

我们之前曾报道过肠上皮细胞 (IEC)中组蛋白去乙酰化酶表观遗传调节因子Hdac1和Hdac2 的缺失会破坏粘膜组织结构和屏障，导致慢性炎症。在这项研究中，蛋白质组和转录组分析揭示了对遗传 IEC- Hdac1和Hdac2诱导的信号通路的重要性删除。事实上，基因本体论对富集缺陷 IEC RNA 和蛋白质的生物过程分析确定了与免疫反应相关的常见途径，包括脂质代谢和氧化还原过程、细胞粘附和抗原加工和呈递，与主要组织相容性复合体 (MHC) 的失调相关) II 类基因。顶级上游监管机构包括与环境传感途径相关的监管机构，包括异生素、微生物和饮食衍生的配体以及内源性代谢物。蛋白质组分析揭示了 mTOR 信号传导 IEC 特定的缺陷。除 mTOR 外，STAT 和 Notch 通路在空肠 IEC 中特别失调。为了确定通路失调对突变空肠改变的影响，我们用 JAK 抑制剂托法替尼治疗突变小鼠。用抑制剂处理部分纠正了增殖和紧密连接缺陷，以及通过增加 Paneth 细胞数量来稳定生态位。因此，IEC 特异性组蛋白去乙酰化酶 1 (HDAC1) 和 2 (HDAC2) 通过调节存活和翻译过程以及分化和代谢途径来支持肠道稳态。HDAC1 和 HDAC2 可能通过直接或间接控制 JAK/STAT 通路在 IEC 特异性炎症反应的调节中发挥重要作用。IEC 特异性 JAK/STAT 通路失调可能至少部分是造成突变小鼠肠道稳态破坏的原因。IEC 特异性组蛋白去乙酰化酶 1 (HDAC1) 和 2 (HDAC2) 通过调节存活和翻译过程以及分化和代谢途径来支持肠道稳态。HDAC1 和 HDAC2 可能通过直接或间接控制 JAK/STAT 通路在 IEC 特异性炎症反应的调节中发挥重要作用。IEC 特定的 JAK/STAT 通路失调可能至少部分是造成突变小鼠肠道稳态破坏的原因。IEC 特异性组蛋白去乙酰化酶 1 (HDAC1) 和 2 (HDAC2) 通过调节存活和翻译过程以及分化和代谢途径来支持肠道稳态。HDAC1 和 HDAC2 可能通过直接或间接控制 JAK/STAT 通路在 IEC 特异性炎症反应的调节中发挥重要作用。IEC 特定的 JAK/STAT 通路失调可能至少部分是造成突变小鼠肠道稳态破坏的原因。