Single cell transcriptomic analysis in a mouse model of Barth syndrome reveals cell-specific alterations in gene expression and intercellular communication

Perera, G., Power, L., Larson, A., Codden, C. J., Awata, J., Batorsky, R., Strathdee, D. and Chin, M. T. (2023) Single cell transcriptomic analysis in a mouse model of Barth syndrome reveals cell-specific alterations in gene expression and intercellular communication. International Journal of Molecular Sciences, 24(14), 11594. (doi: 10.3390/ijms241411594) (PMID:37511352) (PMCID:PMC10380964)

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Abstract

Barth Syndrome, a rare X-linked disorder affecting 1:300,000 live births, results from defects in Tafazzin, an acyltransferase that remodels cardiolipin and is essential for mitochondrial respiration. Barth Syndrome patients develop cardiomyopathy, muscular hypotonia and cyclic neutropenia during childhood, rarely surviving to middle age. At present, no effective therapy exists, and downstream transcriptional effects of Tafazzin dysfunction are incompletely understood. To identify novel, cell-specific, pathological pathways that mediate heart dysfunction, we performed single-nucleus RNA-sequencing (snRNA-seq) on wild-type (WT) and Tafazzin-knockout (Taz-KO) mouse hearts. We determined differentially expressed genes (DEGs) and inferred predicted cell–cell communication networks from these data. Surprisingly, DEGs were distributed heterogeneously across the cell types, with fibroblasts, cardiomyocytes, endothelial cells, macrophages, adipocytes and pericytes exhibiting the greatest number of DEGs between genotypes. One differentially expressed gene was detected for the lymphatic endothelial and mesothelial cell types, while no significant DEGs were found in the lymphocytes. A Gene Ontology (GO) analysis of these DEGs showed cell-specific effects on biological processes such as fatty acid metabolism in adipocytes and cardiomyocytes, increased translation in cardiomyocytes, endothelial cells and fibroblasts, in addition to other cell-specific processes. Analysis of ligand–receptor pair expression, to infer intercellular communication patterns, revealed the strongest dysregulated communication involved adipocytes and cardiomyocytes. For the knockout hearts, there was a strong loss of ligand–receptor pair expression involving adipocytes, and cardiomyocyte expression of ligand–receptor pairs underwent reorganization. These findings suggest that adipocyte and cardiomyocyte mitochondria may be most sensitive to mitochondrial Tafazzin deficiency and that rescuing adipocyte mitochondrial dysfunction, in addition to cardiomyocyte mitochondrial dysfunction, may provide therapeutic benefit in Barth Syndrome patients.

Item Type:Articles
Additional Information:M.C.’s research laboratory was funded by the National Institutes of Health, grant numbers 1 R61 HL154137-01A1 and 1 R01 HL159436. L.P. was funded by National Institutes of Health, grant number 5T32GM008448-26.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Strathdee, Mr Douglas
Authors: Perera, G., Power, L., Larson, A., Codden, C. J., Awata, J., Batorsky, R., Strathdee, D., and Chin, M. T.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:International Journal of Molecular Sciences
Publisher:MDPI
ISSN:1661-6596
ISSN (Online):1422-0067
Published Online:18 July 2023
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in International Journal of Molecular Sciences 24(14): 11594
Publisher Policy:Reproduced under a Creative Commons License

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