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Abstract 510: Spatial Transcriptomics Unveil ZBTB11 as a Regulator of Cardiomyocyte Degeneration in Arrhythmogenic Cardiomyopathy


 Introduction:
 Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder characterized by progressive loss of contractile myocardium which is replaced by fibrous and adipose tissue, ventricular arrhythmias, and sudden cardiac death. Fibrofatty replacement extends transmurally with an epi-to-endocardial gradient, yet molecular differences between the transition regions are poorly characterized.
 
 
 Methods and Results:
 To explore molecular mechanisms underlying ACM we obtained an explanted heart of a 35-year-old male with a known pathogenic
 PKP2
 mutation, c.2544G>A. We utilized Tomo-Seq to acquire a genome-wide transcriptional profile with 100μm-spatial resolution, generating a transmural expression atlas of the ACM heart. Tracing transcriptional differences across the ventricular wall enabled us to identify clusters of genes specific to the myocardium and fibrofatty region. In addition, we detected restricted sites of active remodelling within the myocardium with a clearly distinct gene program. Amongst genes specifically enriched in this composite region was the Zinc Finger and BTB Domain-Containing Protein 11 (ZBTB11). Overexpression of ZBTB11 in human cardiomyocytes induced a differential gene expression profile with striking similarities to the composite region from the Tomo-Seq analysis. Most notably, ZBTB11 induced a TP53 mediated stress response including activation of apoptosis and autophagy. The presence of ZBTB11-positive cardiomyocytes flanking fibrofatty islands was confirmed in ACM patients harbouring other
 PKP2
 mutations, as well as ACM and DCM hearts with mutations in non-desmosomal genes. We are currently exploring the ZBTB11 transcriptional network, and its role in disease progression in human cardiomyopathies.
 
 
 Conclusions:
 Using a spatial transcriptomics approach on a human ACM heart we have identified ZBTB11 as a novel marker of cardiomyocyte degeneration in cardiomyopathies. ZBTB11 induces autophagy and apoptosis and therefore may be relevant for the development of biomarker assays and in identifying novel targets for therapies against cardiomyopathies.
