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

Immunobiology. 2020 May;225(3):151958. doi: 10.1016/j.imbio.2020.151958. Epub 2020 May 12.

Abstract

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.

Keywords: Cytokine production; Monocyte subsets; NF-κB pathway; Next generation sequencing; Signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • CpG Islands
  • Cytokines / genetics*
  • Cytokines / metabolism
  • DNA Methylation
  • Epigenesis, Genetic*
  • Gene Expression Regulation*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Inflammation Mediators / metabolism
  • Lipopolysaccharides / immunology
  • MicroRNAs / genetics
  • Monocytes / immunology
  • Monocytes / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • RNA, Messenger / genetics
  • Signal Transduction

Substances

  • Biomarkers
  • Carrier Proteins
  • Cytokines
  • Inflammation Mediators
  • Lipopolysaccharides
  • MicroRNAs
  • Nerve Tissue Proteins
  • RNA, Messenger
  • TRIM8 protein, human