Lysophosphatidylcholine promotes trained immunity of human aortic endothelial cells via histone 3 lysine 14 acetylation‐dependent and independent gene modulation

Abstract

We previously reported that a conditional danger associated molecular pattern (conditional DAMP), pro‐atherogenic lipid lysophosphatidylcholine (lysoPC) induces human aortic endothelial cell (HAEC) activation via histone 3 lysine 14 acetylation (H3K14Ac); and HAEC activation plays important role in vascular inflammation and atherosclerotic cardiovascular diseases. However, the mechanisms underlying how lysoPC induced HAEC activation via histone acetylation remain unknown. To examine this issue, we carried out RNA‐Seq of lysoPC‐treated HAEC; and CHIP‐Seq using antibody to H3K14Ac in lysoPC‐treated HAEC. By analyzing the RNA‐Seq and CHIP‐Seq data, we found out the following results: 1) lysoPC modulates the expressions of 9 out of 31 histone acetyltransferases (HATs) with 6 increased and 3 decreased; and three out of the 6 increased HATs are reported to mediate H3K14Ac; 2) among three Acetyl‐CoA generating enzymes, lysoPC upregulates ACS2 (nucleus) and ACL (cytosol), and decreases ACS1 (peroxisome); 3) lysoPC modulates 5 out of 9 glycolytic enzymes with 3 increased and 2 decreased; and increases 6 out of 7 mevalonate pathway enzymes; 4) lysoPC increases the expressions of both T cell costimulation ligands and receptors; 5) lysoPC‐induced H3K14Ac increases the frequencies of downstream chromatin long range interactions (CLRIs); and lysoPC potentially‐induced other histone acetylations prefer to modulate upstream CLRIs. Our findings have demonstrated that lysoPC promotes HAEC activation and gene modulations via increasing acetylation of H3K14 and potential other histone lysines, and thereby frequencies of chromatin long‐range gene interactions, which significantly enhance newly characterized trained immunity features of HAEC. Our results provide novel therapeutic targets for controlling endothelial cell activation, vascular inflammation, and cardiovascular diseases.Support or Funding InformationThis work was supported by NIH grant to Drs. XF. Yang, H. Wang.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.