The Sry-related high-mobility-group box (SOX) gene family, with 20 known transcription
factors in humans, plays an essential role during development and disease processes.
Several SOX proteins (SOX4, 11, and 9) are required for normal heart morphogenesis.
SOX9 was shown to contribute to cardiac fibrosis. However, differential expression
of other SOXs and their roles in the failing human myocardium have not been explored.
Here, we used the whole-transcriptome sequencing (RNA-seq), gene co-expression, and
meta-analysis to examine whether any SOX factors might play a role in the failing
human myocardium. RNA-seq analysis was performed for cardiac tissue samples from heart
failure (HF) patients due to dilated cardiomyopathy (DCM), or hypertrophic cardiomyopathy
(HCM) and healthy donors (NF). The RNA levels of 20 SOX genes from RNA-seq data were
extracted and compared to the 3 groups. Four SOX genes whose RNA levels were significantly
upregulated in DCM or HCM compared to NF. However, only SOX4 and SOX8 proteins were
markedly increased in the HF groups. A moderate to strong correlation was observed
between the RNA level of SOX4/8 and fibrotic genes among each individual. Gene co-expression
network analysis identified genes associated and respond similarly to perturbations
with SOX4 in cardiac tissues. Using a meta-analysis combining epigenetics and genome-wide
association data, we reported several genomic variants associated with HF phenotype
linked to SOX4 or SOX8. In summary, our results implicate that SOX4 and SOX8 have
a role in cardiomyopathy, leading to HF in humans. The molecular mechanism associated
with them in HF warrants further investigation.
Abbreviations:
CLEC11A (C-type lectin domain containing 11A), DCM (Dilated cardiomyopathy), DPYSL3 (dihydropyrimidinase-related protein 3), ELK3 (ETS transcription factor 3), GWAS (Genome-wide association study), HCM (hypertrophic cardiomyopathy (HCM)), HF (Heart failure), LMF1 (Lipase Maturation Factor 1), MAGNet (Myocardial Applied Genomics Network), NF (non-failing), PTM (Post-translational modifications), RAI14 (Retinoic acid-induced protein 14), RCN3 (Reticulocalbin-3), SOX (Sry-related high-mobility-group box), TF (Transcription factor), TPM (Transcripts Per Kilobase Million)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: October 22, 2021
Accepted:
October 15,
2021
Received in revised form:
October 9,
2021
Received:
November 9,
2020
Footnotes
Featured New Investigator: Chia-Feng Liu, PhD, is a Research Associate in the Department of Cardiovascular and Metabolic Sciences at the Cleveland Clinic's Learner Research Institute.
Identification
Copyright
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