Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

A Superenhancer containing Inhibitor of DNA-Binding 1 protects the heart from metabolic stress
D. Finke1, L. Schanze1, M. Heckmann1, T. Meßmer1, B. Meder1, H.-J. Gröne2, K. Richter2, H. A. Katus1, N. Frey1, L. H. Lehmann1
1Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie, Universitätsklinikum Heidelberg, Heidelberg; 2Deutsches Krebsforschungszentrum (DKFZ), Heidelberg;

Cardiovascular risk factors are mostly attributed to the occurrence of coronary heart disease (CHD). Direct nutritional influences on the cardiac function, e.g. in the context of diabetes have been recently proposed. Nevertheless, there is a lack of knowledge of the cardiac epigenetic regulation and possible imprinting mechanisms after specific diets.

To assess potential sustained epigenetic events in cardiomyocytes, we treated C57BL6 mice with either High Fat Diet (HFD) for 10 weeks or Low Fat Diet (LFD) as a control. We further included a third group on HFD for 5 weeks and ‘reverse feeding’ on LFD for 5 weeks. Based on bodyweight we found a complete recovery of the phenotype (LFD (n=15): 27.76g ± 0.37g, HFD (n=15): 32.93g ± 0.59g, Reverse (n=15): 28.01g ± 0.67g; mean ± SEM). On the epigenetic level, we found 330 H3K27ac+ enhancers after HFD in ChIP-seq experiments of isolated cardiomyocytes (DESeq2, FDR < 0.1). Of these, only one large superenhancer (SE), containing the coding gene of Inhibitor of DNA-Binding 1 (ID1), was persistently activated after reverse feeding.

To further investigate the biological relevance of this region, we generated a cardiomyocyte-specific knockout mouse line (ID1-cKO). ID1-cKO showed a preserved left ventricular ejection fraction (LVEF) under LFD (LVEF mean ± SEM WT (n=8) 79.6%±3.5%, ID1 cKO: (n=8) 79.2%±2.4%, p=0.72, Mann-Whitney Test) and a significant deterioration under HFD (LVEF mean ± SEM WT (n=10): 77.6%±2.0%, ID1-cKO (n=8): 66.8%±3.4%, p=0.016, Mann-Whitney Test) which was maintained after reverse feeding (LVEF mean ± SEM WT (n=12): 76.9%±2.1%, ID1-cKO (n=10): 65.1%±4.0%, p=0.02, Mann-Whitney Test). On a transcriptional level, HFD lead to a significantly upregulation of a gene program in the heart of cre+ controls animals (FDR<0.05) but not in ID1-cKO (FRD>0.05). These genes (e.g., Pdk4, Acot3, Cpt1b and Gpam) are known to regulate fatty acid metabolism (FAM). As a potential upstream activator, we identified the transcription factor binding motif of nr1F1 (nuclear receptor 1F1) highly overrepresented in the promoter regions (p=1e-13) with potential binding site in all ID1-dependent FAM-genes. These results may be linked to dysmorphic mitochondria, detected via electron microscopy in ID1-cKO under HFD. Missing PGC1a upregulation in ID1-cKO subjected to catecholaminergic stress of isoprenaline/phenylephrine supports the hypothesis of a mitochondria- and FAM-related cardiac phenotype in ID1-cKO (fc 1.5 in WT ISO/PE (n=8) vs. WT control (n=7) vs. 1.2 in ID1-cKO (n=7); p<0.001 ANOVA+Bonferroni post-test).

We identified an epigenetic imprint that is correlated with adaptive FAM and the maintenance of LVEF upon HFD. Ongoing studies in cKO animals of non-coding regions of the HFD-dependent SE will allow us to understand this epigenetic phenomenon in more detail.


https://dgk.org/kongress_programme/jt2022/aP440.html