Genome-wide localization of the polyphenol quercetin in human monocytes

Abstract

Background: Quercetin is a polyphenol of great interest given its antioxidant activity and involvement in the immune response. Although quercetin has been well studied at the molecular level as a gene regulator and an activator of specific cellular pathways, not much attention has been given to its mechanism of action at the genome-wide level. The present study aims to characterize quercetin's interaction with cellular DNA and to show its subsequent effect on downstream transcription.

Results: Two massive parallel DNA-sequencing technologies were used: Chem-seq and RNA-seq. We demonstrate that upon binding to DNA or genome-associated proteins, quercetin acts as a cis-regulatory transcription factor for the expression of genes that are involved in the cell cycle, differentiation and development.

Conclusions: Such findings could provide new and important insights into the mechanisms by which the dietary polyphenol quercetin influences cellular functions.

Keywords: Anticancer; Chem-seq; Polyphenol; Quercetin; RNA-seq.

Fig. 1

Synthesis of biotinylated quercetin. The biotinylated quercetin was synthesized in 5 steps (see Methods), and compounds are labeled from 1 to 6

Fig. 2

Colocalization of quercetin beads with DNA and the 1,000 most significant peaks across the genome. a Structure of biotinylated quercetin product. b Flowchart of Chem-seq procedure. c Gene ontology (GO) enrichment of the 36 genes associated to the quercetin peaks up to 500 bp from the transcription start site. Bead peaks did not tend to cluster into any functional category. d Motif enrichment in quercetin and bead (control) treatments. Bead motif enrichment did not result in any significant motif hit

Fig. 3

Distribution of P values and FC values of gene expression before and after quercetin treatment. a Kernel density estimates of P values obtained from 10 cycles of 100 permutations. P value was obtained by using Kolmogorov–Smirnov test between two sets of 36 FC values. Prandom denotes the distribution of P values for two sets of 36 randomly selected genes. Pempirical denotes the distribution of P values obtained by comparing the empirical FC values to the random set. Illustration suggests that FC induced by quercetin is significantly different than might be expected by chance. b Kernel density estimate of log FC of quercetin and the background set. Illustration suggests that quercetin tends to induce expression levels. Quercetin denotes the FC values of 36 cell-cycle genes. Background denotes the FC values of 16,308 genes (P = 0.02, Kolmogorov–Smirnov test)