Differential Expression of Members of SOX Family of Transcription Factors in Failing Human Hearts.

Chia-Feng Liu, Y. Ng, Varun Thachil, M. Morley, C. Moravec, W. Tang
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引用次数: 5

Abstract

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 three 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. BACKGROUND: : Heart failure (HF) affects 5.7 million people in the U.S. with more than 500,000 new cases added annually. New therapeutic strategies remain needed for HF. The cardiac-pathological features are driven by transcriptome reprogramming. Understanding transcriptional control of HF is beneficial for developing novel therapies. TRANSLATIONAL SIGNIFICANCE: : This study revealed that SOX4 and SOX8 were significantly increased in cardiac tissues of HF patients and the HF-genetic variants and epigenetic changes associated with these two genes. Understanding the role of SOX4 and SOX8 in failing human myocardium and gene regulatory networks related to them may help to identify potential therapeutic targets for HF.
人衰竭心脏中SOX转录因子家族成员的差异表达。
sry相关的高迁移群盒(SOX)基因家族在人类中有20个已知的转录因子,在发育和疾病过程中起着重要作用。几种SOX蛋白(SOX4、11和9)是正常心脏形态发生所必需的。SOX9被证明有助于心脏纤维化。然而,其他SOXs的差异表达及其在人心肌衰竭中的作用尚未探讨。在这里,我们使用全转录组测序(RNA-seq),基因共表达和荟萃分析来检查是否有SOX因素可能在人类心肌衰竭中发挥作用。对扩张型心肌病(DCM)或肥厚型心肌病(HCM)引起的心力衰竭(HF)患者和健康供者(NF)的心脏组织样本进行RNA-seq分析。从RNA-seq数据中提取20个SOX基因的RNA水平,并与三组进行比较。4个SOX基因的RNA水平在DCM或HCM中与NF相比显著上调。而HF组只有SOX4和SOX8蛋白明显升高。在每个个体中,SOX4/8的RNA水平与纤维化基因之间存在中等到强的相关性。基因共表达网络分析确定了与心脏组织中SOX4干扰相关的基因,并对其做出类似的反应。通过结合表观遗传学和全基因组关联数据的荟萃分析,我们报告了与SOX4或SOX8相关的HF表型相关的几个基因组变异。总之,我们的结果表明SOX4和SOX8在心肌病中起作用,导致人类心衰。在HF中与它们相关的分子机制有待进一步研究。背景:心力衰竭(HF)在美国影响着570万人,每年新增病例超过50万。心衰仍然需要新的治疗策略。心脏病理特征是由转录组重编程驱动的。了解心衰的转录控制有助于开发新的治疗方法。翻译意义:本研究揭示了SOX4和SOX8在HF患者心脏组织中显著升高,以及与这两个基因相关的HF遗传变异和表观遗传改变。了解SOX4和SOX8在人类心肌衰竭中的作用以及与之相关的基因调控网络可能有助于确定心衰的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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