Defining the fetal gene program at single cell resolution in dilated cardiomyopathy.

It is hypothesized that the postnatal heart adopts a fetal-like transcriptional state in response to cardiac stress. Here, we analyse the transcriptome of 74,451 nuclei from fetal, non-diseased and early-onset DCM samples, which revealed 7 broad cell clusters across fetal, ND and DCM samples. We find that there are no statistically significant shifts in cellular composition between DCM and ND hearts. Also, pseudo-bulk profiling revealed that transcriptional pathways perturbed in DCM are predominantly associated with cardiomyocytes, fibroblasts and immune cells. We advance the hypothesis that only a small subset (<10%) of fetal genes is re-engaged in both cardiomyocyte and cardiac fibroblast of DCM. This study provides a framework to identify critical gene expression networks that underpin disease pathogenesis independent of genetic aetiology. Overall design: 10x Chromium single nuclei sequencing (snRNA-seq) profiles of apical left ventricle tissue from fetal (19-20 weeks, n=3; 27,760 nuclei), non-diseased (ND; 4-14 years, n=3; 16,964 nuclei) and early-onset DCM samples (5-10 years, n=4; 32,712 nuclei)