In this thesis by Jolien Fledderus, we investigated how epigenetic mechanisms influence the functioning of endothelial cells (ECs) and can lead to problems in the endothelium (a layer of cells on the inside of our blood vessels). We did this by looking at the role of EZH2, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs).
We show that epigenetic regulation, or the way in which genes are turned on and off without changing the DNA sequence, is very important for the normal functioning of endothelial cells. If this regulation is disrupted, it can lead to problems in the endothelium. We have discovered that the protein EZH2, together with the chemical modification H3K27me3, plays an important role in these processes. Increased activity of the protein EZH2 can lead to problems in the endothelium due to the way it controls genes that are important for the function of endothelial cells.
However, we also found that protein EZH2 does not always directly influence gene expression in endothelial cells. This often occurs via intermediaries such as miRNAs and lncRNAs. This shows how complex the epigenetic network is.
In addition, we suggest that inhibiting EZH2 and reducing H3K27me3 in endothelial cells may be a potential therapy to prevent or treat cardiovascular diseases (CVDs). There are already epigenetic drugs, including EZH2 inhibitors, in development or available for use in clinical settings. It is therefore interesting to investigate how these agents can help prevent or treat endothelial problems in the context of cardiovascular disease.
