NFκB p50-CCAAT/enhancer-binding protein β (C/EBPβ)-mediated transcriptional repression of microRNA let-7i following microbial infection

Steven P. O'Hara, Patrick L. Splinter, Gabriella B. Gajdos, Christy E. Trussoni, Martin E. Fernandez-Zapico, Xian-Ming Chen, Nicholas F. LaRusso

Research output: Contribution to journalArticle

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Abstract

MicroRNAs, central players of numerous cellular processes, regulate mRNA stability or translational efficiency. Although these molecular events are established, the mechanisms regulating microRNA function and expression remain largely unknown. The microRNA let-7i regulates Toll-like receptor 4 expression. Here, we identify a novel transcriptional mechanism induced by the protozoan parasite Cryptosporidium parvum and Gram(-) bacteria-derived lipopolysaccharide (LPS) mediating let-7i promoter silencing in human biliary epithelial cells (cholangiocytes). Using cultured cholangiocytes, we show that microbial stimulus decreased let-7i expression, and promoter activity. Analysis of the mechanism revealed that microbial infection promotes the formation of a NFκB p50-C/EBPβ silencer complex in the regulatory sequence. Chromatin immunoprecipitation assays (ChIP) demonstrated that the repressor complex binds to the let-7i promoter following microbial stimulus and promotes histone-H3 deacetylation. Our results provide a novel mechanism of transcriptional regulation of cholangiocyte let-7i expression following microbial insult, a process with potential implications for epithelial innate immune responses in general.

Original languageEnglish
Pages (from-to)216-225
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number1
DOIs
StatePublished - Jan 1 2010

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CCAAT-Enhancer-Binding Proteins
MicroRNAs
Infection
Cryptosporidium parvum
Toll-Like Receptor 4
Chromatin Immunoprecipitation
RNA Stability
Innate Immunity
Histones
Chromatin
Lipopolysaccharides
Assays
Bacteria
Parasites
Epithelial Cells
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

NFκB p50-CCAAT/enhancer-binding protein β (C/EBPβ)-mediated transcriptional repression of microRNA let-7i following microbial infection. / O'Hara, Steven P.; Splinter, Patrick L.; Gajdos, Gabriella B.; Trussoni, Christy E.; Fernandez-Zapico, Martin E.; Chen, Xian-Ming; LaRusso, Nicholas F.

In: Journal of Biological Chemistry, Vol. 285, No. 1, 01.01.2010, p. 216-225.

Research output: Contribution to journalArticle

O'Hara, Steven P. ; Splinter, Patrick L. ; Gajdos, Gabriella B. ; Trussoni, Christy E. ; Fernandez-Zapico, Martin E. ; Chen, Xian-Ming ; LaRusso, Nicholas F. / NFκB p50-CCAAT/enhancer-binding protein β (C/EBPβ)-mediated transcriptional repression of microRNA let-7i following microbial infection. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 1. pp. 216-225.
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