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,
Yu Sun,
Charles Drummer, IV,
Gayani K. Nanayakkara,
Ying Shao,
Fatma Saaoud,
Candice Johnson,
Ruijing Zhang,
Daohai Yu,
Xinyuan Li,
William Y. Yang,
Jun Yu,
Xiaohua Jiang,
Eric T. Choi,
Hong Wang,
Xiaofeng Yang
Affiliations
Yifan Lu
Centers for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Yu Sun
Centers for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Charles Drummer, IV
Centers for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Gayani K. Nanayakkara
Centers for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Ying Shao
Centers for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Fatma Saaoud
Centers for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Candice Johnson
Centers for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Ruijing Zhang
Centers for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Daohai Yu
Department of Clinical Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Xinyuan Li
Centers for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
William Y. Yang
Centers for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Jun Yu
Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Xiaohua Jiang
Centers for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Eric T. Choi
Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Division of Vascular & Endovascular Surgery, Department of Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Hong Wang
Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Department of Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA
Xiaofeng Yang
Centers for Inflammation, Translational & Clinical Lung Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Cardiovascular Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Department of Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA; Corresponding author. Centers for Inflammation, Translational & Clinical Lung Research, Metabolic Disease Research and Cardiovascular Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
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: Trained immunity, Human aortic endothelial cell activation, Proatherogenic lipids lysophosphatidycholine (LPC), RNA-Seq, Chromatin long range interaction
