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

Cornelis J Boogerd1, Grégory P A Lacraz1, Ábel Vértesy1,2

  • 1Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, The Netherlands.

Cardiovascular Research
|May 16, 2022
PubMed

Insights

Arrhythmogenic cardiomyopathy (ACM) involves fibro-fatty replacement of heart muscle. This study identifies ZBTB11 as a key gene driving cardiomyocyte loss in ACM, revealing new molecular mechanisms.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Cardiac Pathology

Background:

  • Arrhythmogenic cardiomyopathy (ACM) is an inherited heart condition characterized by progressive myocardial degeneration and fibro-fatty replacement, leading to arrhythmias and sudden cardiac death.
  • The precise molecular mechanisms underlying regional myocardial remodeling in ACM remain poorly understood.

Purpose of the Study:

  • To delineate local gene expression changes in ACM to identify novel genes and pathways involved in specific disease remodeling processes.
  • To gain molecular insights into disease-driving mechanisms using high-resolution spatial transcriptomics.

Main Methods:

  • Utilized Tomo-Seq, a genome-wide transcriptional profiling technique with high spatial resolution, on explanted ACM hearts.
  • Created transmural epicardial-to-endocardial gene expression atlases to link gene expression profiles with regional remodeling.
  • Performed immunohistochemistry to validate gene expression findings in patient samples.

Main Results:

  • Identified distinct gene expression profiles associated with cardiomyocyte degeneration and fibro-fatty remodeling.
  • Discovered Zinc finger and BTB domain-containing protein 11 (ZBTB11) to be specifically enriched at sites of active fibro-fatty replacement.
  • Demonstrated that ZBTB11 overexpression in human cardiomyocytes induces autophagy, cell death pathways, and apoptosis.

Conclusions:

  • Tomo-Seq is a powerful tool for uncovering novel molecular mechanisms in human cardiomyopathy.
  • ZBTB11 is identified as a novel molecular driver of cardiomyocyte loss in arrhythmogenic cardiomyopathy.
Abstract

Keywords:
Arrhythmogenic cardiomyopathyCardiomyocyte degenerationTomo-SeqZBTB11

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