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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References
- Global public health burden of heart failure.Card Fail Rev. 2017; 3: 7-11
- Cardiac remodeling: concepts, clinical impact, pathophysiological mechanisms and pharmacologic treatment.Arq Bras Cardiol. 2016; 106: 62-69
- Transcriptome complexity in cardiac development and diseases–an expanding universe between genome and phenome.Circ J. 2014; 78: 1038-1047
- Sox proteins: regulators of cell fate specification and differentiation.Development. 2013; 140: 4129-4144
- SOXopathies: growing family of developmental disorders due to SOX mutations.Trends Genet. 2019; 35: 658-671
- Sox6 regulation of cardiac myocyte development.Nucleic Acids Res. 2003; 31: 5941-5948
- Tomo-Seq identifies SOX9 as a key regulator of cardiac fibrosis during ischemic injury.Circulation. 2017; 136: 1396-1409
- Inactivation of Sox9 in fibroblasts reduces cardiac fibrosis and inflammation.JCI Insight. 2019; 4e126721https://doi.org/10.1172/jci.insight.126721
- Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.Lancet Respir Med. 2019; 7: 227-238
- Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease.Genome Med. 2018; 10: 56
- Whole-transcriptome profiling of human heart tissues reveals the potential novel players and regulatory networks in different cardiomyopathy subtypes of heart failure.Circ Genom Precis Med. 2021; 14e003142
- RNA-Seq identifies novel myocardial gene expression signatures of heart failure.Genomics. 2015; 105: 83-89
- Global analysis of histone modifications and long-range chromatin interactions revealed the differential cistrome changes and novel transcriptional players in human dilated cardiomyopathy.J Mol Cell Cardiol. 2020; 145: 30-42
- STAR: ultrafast universal RNA-seq aligner.Bioinformatics. 2013; 29: 15-21
- RNA-seq analysis is easy as 1-2-3 with limma.Glimma and edgeR. 2018; 5 (F1000Res)1408
- NetworkAnalyst 3.0: a visual analytics platform for comprehensive gene expression profiling and meta-analysis.Nucleic Acids Res. 2019; 47: W234-WW41
- Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.Genome Biol. 2009; 10: R25
- Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities.Mol Cell. 2010; 38: 576-589
- Integrative analysis of 111 reference human epigenomes.Nature. 2015; 518: 317-330
- Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.Nat Commun. 2020; 11: 163
CVDKP. Cardiovascular Disease Knowledge Portal. [cited 2020 June 5]. Available from: http://www.broadcvdi.org/.
- CTGF/CCN2 is an autocrine regulator of cardiac fibrosis.J Mol Cell Cardiol. 2018; 121: 205-211
- Increased collagen type I synthesis in patients with heart failure of hypertensive origin: relation to myocardial fibrosis.Circulation. 2004; 110: 1263-1268
- Lysyl oxidase directly contributes to extracellular matrix production and fibrosis in systemic sclerosis.Am J Physiol Lung Cell Mol Physiol. 2021; 320: L29-L40
- Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease.J Clin Invest. 2009; 119: 1438-1449
- Activation of Wnt11 by transforming growth factor-beta drives mesenchymal gene expression through non-canonical Wnt protein signaling in renal epithelial cells.J Biol Chem. 2012; 287: 21290-21302
- SOX8 regulates cancer stem-like properties and cisplatin-induced EMT in tongue squamous cell carcinoma by acting on the Wnt/beta-catenin pathway.Int J Cancer. 2018; 142: 1252-1265
- EZH2 as a novel therapeutic target for atrial fibrosis and atrial fibrillation.J Mol Cell Cardiol. 2019; 135: 119-133
- Snail1 is involved in de novo cardiac fibrosis after myocardial infarction in mice.Acta Biochim Biophys Sin (Shanghai). 2012; 44: 902-910
- Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis.Elife. 2018; 7e27706
- Chemical genomics reveals histone deacetylases are required for core regulatory transcription.Nat Commun. 2019; 10: 3004
- DPYSL3 modulates mitosis, migration, and epithelial-to-mesenchymal transition in claudin-low breast cancer.Proc Natl Acad Sci U S A. 2018; 115 (E11978-E87)
- Differential proteomics identifies reticulocalbin-3 as a novel negative mediator of collagen production in human cardiac fibroblasts.Sci Rep. 2017; 7: 12192
- Gene expression profiling of pulmonary fibrosis identifies Twist1 as an antiapoptotic molecular "rectifier" of growth factor signaling.Am J Pathol. 2009; 175: 2351-2361
- SOX4 mediates TGF-beta-induced expression of mesenchymal markers during mammary cell epithelial to mesenchymal transition.PLoS One. 2013; 8: e53238
- Expression of collagen VI alpha5 and alpha6 chains in human muscle and in Duchenne muscular dystrophy-related muscle fibrosis.Matrix Biol. 2012; 31: 187-196
- Elk-3 is a transcriptional repressor of nitric-oxide synthase 2.J Biol Chem. 2003; 278: 39572-39577
- Inducible nitric oxide synthase and tumor necrosis factor-alpha in myocardium in human dilated cardiomyopathy.J Am Coll Cardiol. 1997; 29: 716-724
- The role of SOX family members in solid tumours and metastasis.Semin Cancer Biol. 2020; 67: 122-153
- SoxE factors: transcriptional regulators of neural differentiation and nervous system development.Semin Cell Dev Biol. 2017; 63: 35-42
- SOX E genes: SOX9 and SOX8 in mammalian testis development.Int J Biochem Cell Biol. 2010; 42: 433-436
- Loss of Sox9 in cardiomyocytes delays the onset of cardiac hypertrophy and fibrosis.Int J Cardiol. 2019; 282: 68-75
- Inflammatory cytokines stabilize SOXC transcription factors to mediate the transformation of fibroblast-like synoviocytes in arthritic disease.Arthritis Rheumatol. 2018; 70: 371-382
- Mechanisms of fibrosis: therapeutic translation for fibrotic disease.Nat Med. 2012; 18: 1028-1040
- Targeting transcription factors for therapeutic benefit.Mol Biosyst. 2008; 4: 909-919
- Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice.Elife. 2017; 6e21221
- Systematic and quantitative assessment of the ubiquitin-modified proteome.Mol Cell. 2011; 44: 325-340
- Acetylation and deacetylation of non-histone proteins.Gene. 2005; 363: 15-23
- KAT5-mediated SOX4 acetylation orchestrates chromatin remodeling during myoblast differentiation.Cell Death Dis. 2015; 6: e1857
Article Info
Publication History
Published online: October 22, 2021
Accepted:
October 15,
2021
Received in revised form:
October 9,
2021
Received:
November 9,
2020
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2021 Elsevier Inc. All rights reserved.
