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.
| Original language | English |
|---|---|
| Article number | 606 |
| Journal | BMC Genomics |
| Volume | 20 |
| Issue number | 1 |
| DOIs | |
| State | Published - 23 Jul 2019 |
Bibliographical note
Publisher Copyright:© 2019 The Author(s).
Funding
P = 0.02). Our list of candidate genes was consistent with the literature showing that quercetin exerts a direct, proapoptotic effect in tumor cells and may block the growth of several human cancer cell lines at different phases of the cell cycle. Both of these effects have been documented in a wide variety of cellular models as well as in animal models. Quercetin’s high toxicity to cancer cells perfectly matches the nearly complete absence of any damage in normal, nontransformed cells [27]. We also found that such regions are enriched with DNA motifs of the transcription factor family E2F (Fig. 2d) with particular similarity to the transcription factor E2F7 which is known to be involved in the S-phase of cell-cycle regulation [28]. This result is supported by the literature as quercetin is well documented to regulate, directly or indirectly, cell-cycle and anticancer genes; it inhibits tumor necrosis factor (TNF)-induced NF-κB transcription factor [29], activates the FOXO transcription factor family [30], and is involved in transcription factor Sp1 function [31]. Moreover, quercetin is known to selectively affect cancer cell proliferation, reduce cyclin D1 activity, induce G1 phase arrest and cause tumor regression by activating the mitochondrial apoptotic pathway [10]. Some of the 36 genes that are postulated to be under cis-regulation of quercetin have been previously reported. For example, the FOXO transcription factor family [30]: 2 genes on our candidate gene list belong to the FOXO transcription factors (FOXD1 and FOXJ1; FC > 2) and may be under direct regulation of quercetin. In addition, our candidate gene list includes 4 collagen genes (COL12A1, COL19A1, COL1A1 and COL2A1; FC > 3); quercetin is involved in collagen family gene regulation [32] and is central to skeletal fragility [33] and the cell cycle [34]. Moreover, our list includes 2 genes belonging to the mitogen-activated protein kinases, MAPK14 and MAPK9, FC > 10. Those genes are well known for their involvement in resistance to colon cancer, cell-cycle arrest and cell death [35, 36].
| Funders | Funder number |
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| Sp1 |
Keywords
- Anticancer
- Chem-seq
- Polyphenol
- Quercetin
- RNA-seq