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Spatial transcriptomics unveils ZBTB11 as a regulator of cardiomyocyte degeneration in arrhythmogenic cardiomyopathy

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Item Type:Article
Title:Spatial transcriptomics unveils ZBTB11 as a regulator of cardiomyocyte degeneration in arrhythmogenic cardiomyopathy
Creators Name:Boogerd, C.J. and Lacraz, G.P.A. and Vértesy, Á. and van Kampen, S.J. and Perini, I. and de Ruiter, H. and Versteeg, D. and Brodehl, A. and van der Kraak, P. and Giacca, M. and de Jonge, N. and Junker, J.P. and van Oudenaarden, A. and Vink, A. and van Rooij, E.
Abstract:AIMS: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that is characterized by progressive loss of myocardium that is replaced by fibro-fatty cells, arrhythmias, and sudden cardiac death. While myocardial degeneration and fibro-fatty replacement occur in specific locations, the underlying molecular changes remain poorly characterized. Here we aim to delineate local changes in gene expression to identify new genes and pathways that are relevant for specific remodelling processes occurring during ACM. METHODS AND RESULTS: Using Tomo-Seq, genome-wide transcriptional profiling with high spatial resolution, we created transmural epicardial to endocardial gene expression atlases of explanted ACM hearts to gain molecular insights into disease-driving processes. This enabled us to link gene expression profiles to the different regional remodelling responses and allowed us to identify genes that are potentially relevant for disease progression. In doing so, we identified distinct gene expression profiles marking regions of cardiomyocyte degeneration and fibro-fatty remodelling and revealed Zinc finger and BTB domain-containing protein 11 (ZBTB11) to be specifically enriched at sites of active fibro-fatty replacement of myocardium. Immunohistochemistry indicated ZBTB11 to be induced in cardiomyocytes flanking fibro-fatty areas, which could be confirmed in multiple cardiomyopathy patients. Forced overexpression of ZBTB11 induced autophagy and cell death-related gene programs in human cardiomyocytes, leading to increased apoptosis. CONCLUSIONS: Our study shows the power of Tomo-Seq to unveil new molecular mechanisms in human cardiomyopathy and uncovers ZBTB11 as a novel driver of cardiomyocyte loss.
Keywords:Tomo-Seq, Arrhythmogenic Cardiomyopathy, Cardiomyocyte Degeneration, ZBTB11
Source:Cardiovascular Research
Publisher:Oxford University Press
Page Range:477-491
Date:February 2023
Official Publication:https://doi.org/10.1093/cvr/cvac072
PubMed:View item in PubMed

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