Epigenetics in non-classical monocytes support their pro-inflammatory gene expression.

  • Cardiovascular Research Unit
May 01, 2020 By:
  • Zhang L
  • Hofer TP
  • Zawada AM
  • Rotter B
  • Krezdorn N
  • Noessner E
  • Devaux Y
  • Heine G
  • Ziegler-Heitbrock L.

Non-classical human monocytes are characterized by high-level expression of cytokines like TNF, but the mechanisms involved are elusive. We have identified miRNAs and CpG-methylation sites that are unique to non-classical monocytes, defined via CD14 and CD16 expression levels. For down-regulated miRNAs that are linked to up-regulated mRNAs the dominant gene ontology term was intracellular signal transduction. This included down-regulated miRNA-20a-5p and miRNA-106b-5p, which both are linked to increased mRNA for the TRIM8 signaling molecule. Methylation analysis revealed 16 hypo-methylated CpG sites upstream of 14 differentially increased mRNAs including 2 sites upstream of TRIM8. Consistent with a positive role in signal transduction, high TRIM8 levels went along with high basal TNF mRNA levels in non-classical monocytes. Since cytokine expression levels in monocytes strongly increase after stimulation with toll-like-receptor ligands, we have analyzed non-classical monocytes (defined via slan expression) after stimulation with lipopolysaccharide (LPS). LPS-stimulated cells continued to have low miRNA-20a and miRNA-106b and high TRIM8 mRNA levels and they showed a 10-fold increase in TNF mRNA. These data suggest that decreased miRNAs and CpG hypo-methylation is linked to enhanced expression of TRIM8 and that this can contribute to the increased TNF levels in non-classical human monocytes.

2020 May. Immunobiology.225(3):151958.
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