Whole genome epigenetic sequencing on DNA from infarcted non-infarcted left ventricle of WT and NEIL3-deficient mice subjected to myocardial infarction

Myocardial infarction (MI) triggers a reparative response involving fibroblast proliferation and differentiation driving extracellular matrix modulation necessary to form a stabilizing scar. Recently, it was shown that a genetic variant of the base excision repair enzyme endonuclease VIII-like 3 (NEIL3) was associated with increased risk of MI in humans. Here, we report elevated myocardial NEIL3 expression in heart failure patients and marked myocardial upregulation of Neil3 following MI in mice, especially in a fibroblast-enriched cell fraction. Neil3-/-mice showed increased mortality after MI compared to WT, caused by myocardial rupture. Epigenomic analysis suggested dysregulated myofibroblast proliferation and differentiation in Neil3-/-hearts and several differentially expressed genes were downstream targets of differentially methylated/hydroxymethylated transcriptional regulators. Furthermore, proliferation of Vimentin+ and SMA+ (myo)fibroblasts was increased in Neil3 -/-hearts following MI. We propose that NEIL3-dependent modulation of epigenetic DNA methylation regulates cardiac fibroblast proliferation and thereby controls extracellular matrix modulation after MI.