Epithelial NELF guards intestinal barrier function to ameliorate colitis by maintaining junctional integrity.
Epithelial NELF guards intestinal barrier function to ameliorate colitis by maintaining junctional integrity.
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DOI：
10.1038/s41385-021-00465-9
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发表时间：
2022-03
影响因子：
8
通讯作者：
Guo XK
中科院分区：
文献类型：
--
作者：
Ou J;Guan X;Wang J;Wang T;Zhang B;Li R;Xu H;Hu X;Guo XK
肠上皮细胞（IEC）中精心策划的转录程序对于维持最佳粘膜屏障功能至关重要，而延长相关机制对屏障功能的贡献仍然未知。在这里，遗传和基因组方法的组合定义了IEC-内在负延伸因子（NELF）复合物在维持上皮稳态中的关键作用。通过直接占据内源性基因位点，NELF持续表达与连接完整性相关的基因子集。因此，上皮NELF缺陷导致这些连接相关基因的水平降低，体内继发于肠道微生物入侵的过度IEC坏死性凋亡。在结肠炎模型中，NELF缺陷小鼠表现出严重受损的屏障完整性，其特征是肠通透性增加，并显著加剧了具有致命后果的肠道炎症。我们的研究结果揭示了NELF复合物对肠道损伤和炎症的保护功能，并表明延长是定义IEC转录组的生物学重要步骤。
Well-orchestrated transcriptional programs in intestinal epithelial cells (IECs) are essential for maintenance of optimal mucosal barrier functions, whereas the contribution of elongation-related mechanisms to barrier function remains unknown. Here, a combination of genetic and genomic approaches defined a critical role of IEC-intrinsic negative elongation factor (NELF) complex in maintenance of epithelial homeostasis. By direct occupancy at endogenous gene loci, NELF sustained expression of a subset of genes related to junctional integrity. As a result, epithelial NELF deficiency results in subdued levels of these junction-related genes and excessive IEC necroptosis in vivo secondary to commensal microbial invasion. In a colitis model, NELF-deficient mice exhibited severely impaired barrier integrity characterized by increased intestinal permeability and significantly exacerbated intestinal inflammation with lethal consequences. Our findings reveal the protective function of the NELF complex against intestinal damage and inflammation and suggest that elongation represents a biologically important step in defining IEC transcriptome.
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期刊：
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DOI：
10.1073/pnas.1309898110
发表时间：
2013-09-03
影响因子：
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