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. 2019 Jun:24:101221.
doi: 10.1016/j.redox.2019.101221. Epub 2019 May 22.

Increased acetylation of H3K14 in the genomic regions that encode trained immunity enzymes in lysophosphatidylcholine-activated human aortic endothelial cells - Novel qualification markers for chronic disease risk factors and conditional DAMPs

Yifan Lu  1 , Yu Sun  1 , Charles Drummer 4th  1 , Gayani K Nanayakkara  1 , Ying Shao  1 , Fatma Saaoud  1 , Candice Johnson  1 , Ruijing Zhang  1 , Daohai Yu  2 , Xinyuan Li  1 , William Y Yang  1 , Jun Yu  3 , Xiaohua Jiang  4 , Eric T Choi  5 , Hong Wang  6 , Xiaofeng Yang  7
Affiliations

Increased acetylation of H3K14 in the genomic regions that encode trained immunity enzymes in lysophosphatidylcholine-activated human aortic endothelial cells - Novel qualification markers for chronic disease risk factors and conditional DAMPs

Yifan Lu et al. Redox Biol. 2019 Jun.

Abstract

To test our hypothesis that proatherogenic lysophosphatidylcholine (LPC) upregulates trained immunity pathways (TIPs) in human aortic endothelial cells (HAECs), we conducted an intensive analyses on our RNA-Seq data and histone 3 lysine 14 acetylation (H3K14ac)-CHIP-Seq data, both performed on HAEC treated with LPC. Our analysis revealed that: 1) LPC induces upregulation of three TIPs including glycolysis enzymes (GE), mevalonate enzymes (ME), and acetyl-CoA generating enzymes (ACE); 2) LPC induces upregulation of 29% of 31 histone acetyltransferases, three of which acetylate H3K14; 3) LPC induces H3K14 acetylation (H3K14ac) in the genomic DNA that encodes LPC-induced TIP genes (79%) in comparison to that of in LPC-induced effector genes (43%) including ICAM-1; 4) TIP pathways are significantly different from that of EC activation effectors including adhesion molecule ICAM-1; 5) reactive oxygen species generating enzyme NOX2 deficiency decreases, but antioxidant transcription factor Nrf2 deficiency increases, the expressions of a few TIP genes and EC activation effector genes; and 6) LPC induced TIP genes(81%) favor inter-chromosomal long-range interactions (CLRI, trans-chromatin interaction) while LPC induced effector genes (65%) favor intra-chromosomal CLRIs (cis-chromatin interaction). Our findings demonstrated that proatherogenic lipids upregulate TIPs in HAECs, which are a new category of qualification markers for chronic disease risk factors and conditional DAMPs and potential mechanisms for acute inflammation transition to chronic ones. These novel insights may lead to identifications of new cardiovascular risk factors in upregulating TIPs in cardiovascular cells and novel therapeutic targets for the treatment of metabolic cardiovascular diseases, inflammation, and cancers. (total words: 245).

Keywords: Chromatin long range interaction; Human aortic endothelial cell activation; Proatherogenic lipids lysophosphatidycholine (LPC); RNA-Seq; Trained immunity.

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Figures

Fig. 1
Fig. 1
LPC induces upregulation of three trained immunity pathways. A. Human aortic endothelial cells (HAECs), treated with lsophosphatidylcholine (LPC), upregulate the three metabolic pathway enzymes, which contribute to trained immunity (innate immune memory). Activated aortic endothelial cells may take shorter time to be activated again when encounter risk factors for the second time. B. 24 acetyl-CoA generating enzymes and 7 mevalonate enzymes are localized in mitochondria, cytosol and nucleus; and three acetyl-CoA generating enzymes (in box) are localized in two subcellular locations.
Fig. 2
Fig. 2
LPC regulates trained immunity by more upregulating metabolic enzymes. A. LPC regulates trained immunity by more upregulating than downregulating metabolic enzymes, suggesting that LPC has the potent in establishing innate immune memory in human aortic endothelial cells. B. The analysis showed that the subcellular locations for LPC regulated acetyl-CoA generating enzymes.
Fig. 3
Fig. 3
LPC-upregulated three histone acetyltransferases all have potential to acetylate histone 3 lysine 14, which is the unique lysine among 10 acetylatable lysine residues in histone 3. LPC-modulated histone acetyltransferases can acetylate potential 25 lysine resides in four histones.
Fig. 4
Fig. 4
Acetylation level of histone 3 lysine 14 residue in the genomic regions of enzymes that mediated trained immunity is higher than that of endothelial cell activation. A. LPC treatment regulates the expression of trained immunity genes and effector genes via H3K14Ac or not; and the 4 groups are compared with pathway analysis and 4c sequencing dataset for long range interaction. B. H3K14Ac regulates 19 trained immunity genes and 51 effector gene; 15 out of 19 genes are increased (78.95%) and 22 out of 51 genes are increased (43.14%).
Fig. 5
Fig. 5
Inter-chromosomal long-range interactions favor LPC induction of trained immunity genes. A. The long-range interaction in upstream promotes trained immunity in LPC treated HAECs. The long-range interaction in upstream is significant different between LPC increased effector genes and decreased effector gene; and between effectors and trained immunity genes. B. Working model of long-range regulation of genes.
Fig. 6
Fig. 6
A novel working model: LPC leads to different trained immunities which are the novel makers for quantification of chronic disease risk factor; and LPC leads to trained immunity through ROS production, H3K14 acetylation and long-range interaction.
figs1
figs1
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