2. Academic Validation
  3. 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

  • Mucosal Immunol. 2022 Feb;15(2):279-288. doi: 10.1038/s41385-021-00465-9.
Jiayao Ou  # 1 2 3 4,  Xiaoxing Guan  # 1 3 5,  Jiali Wang 1 2 3,  Tianjiao Wang 4,  Bin Zhang 1 2 3 4,  Rong Li 6,  Huji Xu 2 4,  Xiaoyu Hu 7 8 9 10,  Xue-Kun Guo 11 12 13 14
Affiliations

Affiliations

  • 1 Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.
  • 2 Tsinghua-Peking Center for Life Sciences, Beijing, China.
  • 3 Beijing Key Laboratory for Immunological Research on Chronic Diseases, Beijing, China.
  • 4 School of Medicine, Tsinghua University, Beijing, China.
  • 5 Department of Pathology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 100045, Beijing, China.
  • 6 Department of Biochemistry & Molecular Medicine School of Medicine & Health Sciences, The George Washington University, 2300 I Street NW, Washington, DC, USA.
  • 7 Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China. xiaoyuhu@tsinghua.edu.cn.
  • 8 Tsinghua-Peking Center for Life Sciences, Beijing, China. xiaoyuhu@tsinghua.edu.cn.
  • 9 Beijing Key Laboratory for Immunological Research on Chronic Diseases, Beijing, China. xiaoyuhu@tsinghua.edu.cn.
  • 10 School of Medicine, Tsinghua University, Beijing, China. xiaoyuhu@tsinghua.edu.cn.
  • 11 Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China. guoxk@tsinghua.edu.cn.
  • 12 Tsinghua-Peking Center for Life Sciences, Beijing, China. guoxk@tsinghua.edu.cn.
  • 13 Beijing Key Laboratory for Immunological Research on Chronic Diseases, Beijing, China. guoxk@tsinghua.edu.cn.
  • 14 School of Medicine, Tsinghua University, Beijing, China. guoxk@tsinghua.edu.cn.
  • # Contributed equally.
PMID: 34697434 DOI: 10.1038/s41385-021-00465-9
Abstract

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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