Spatial transcriptomics unveils ZBTB11 as a regulator of cardiomyocyte degeneration in arrhythmogenic cardiomyopathy.
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IF: 13.081
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Cited by: 8
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Datasets
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Abstract

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. 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 programmes in human cardiomyocytes, leading to increased apoptosis. 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

Spatial Transcriptomics
Tomo-seq
Arrhythmogenic cardiomyopathy
Cardiomyocyte degeneration
Tomo-Seq
ZBTB11

MeSH terms

Humans
Arrhythmias, Cardiac
Arrhythmogenic Right Ventricular Dysplasia
Cardiomyopathies
Myocardium
Myocytes, Cardiac
Transcriptome

Authors

Boogerd, Cornelis J
Lacraz, Grégory P A
Vértesy, Ábel
van Kampen, Sebastiaan J
Perini, Ilaria
de Ruiter, Hesther
Versteeg, Danielle
Brodehl, Andreas
van der Kraak, Petra
Giacca, Mauro
de Jonge, Nicolaas
Junker, Jan Philipp
van Oudenaarden, Alexander
Vink, Aryan
van Rooij, Eva

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