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Mol Cell Biol. 2019 May 6. pii: MCB.00553-18. doi: 10.1128/MCB.00553-18. [Epub ahead of print]

Hypoxic environment promotes barrier formation in human intestinal epithelial cells through regulation of miRNA-320a expression.

Author information

1
Schaller research group at CellNetworks, Department of Infectious Diseases, Virology, Heidelberg University Hospital, Germany.
2
CellNetworks - Cluster of Excellence, Department of Infectious Diseases, Integrative Virology, Heidelberg University Hospital, Germany and German Center for Infection Research (DZIF), Heidelberg, Germany.
3
Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
5
Schaller research group at CellNetworks, Department of Infectious Diseases, Virology, Heidelberg University Hospital, Germany m.stanifer@dkfz.de.
6
Schaller research group at CellNetworks, Department of Infectious Diseases, Virology, Heidelberg University Hospital, Germany s.boulant@dkfz.de.
7
Research Group "Cellular Polarity of Viral Infection", German Cancer Research Center (DKFZ), Heidelberg, Germany.

Abstract

Intestinal epithelial cells (IECs) are exposed to the low-oxygen environment present in the lumen of the gut. These hypoxic conditions are on one hand fundamental for the survival of the commensal microbiota, and on the other hand, favor the formation of a selective semipermeable barrier allowing IECs to transport essential nutrients/water while keeping the sterile internal compartments separated from the lumen containing commensals. The hypoxia-inducible factor (HIF) complex, which allows cells to respond and adapt to fluctuations in oxygen levels, has been described as a key regulator in maintaining IEC barrier function by regulating their tight junction integrity. In this study, we sought to better evaluate the mechanisms by which low oxygen conditions impact the barrier function of human IECs. By profiling miRNA expression in IECs under hypoxia, we identified miRNA-320a as a novel barrier formation regulator. Using pharmacological inhibitors and short hairpin RNA-mediated silencing we could demonstrate that expression of this miRNA was HIF-dependent. Importantly, using over-expression and knock-down approaches of miRNA-320a we could confirm its direct role in the regulation of barrier functions in human IECs. These results reveal an important link between miRNA expression and barrier integrity, providing a novel insight into mechanisms of hypoxia-driven epithelial homeostasis.

PMID:
31061092
DOI:
10.1128/MCB.00553-18

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