SMC3 contributes to heart development by regulating super-enhancer associated genes

IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Experimental and Molecular Medicine Pub Date : 2024-08-01 DOI:10.1038/s12276-024-01293-0
Bowen Zhang, Yongchang Zhu, Zhen Zhang, Feizhen Wu, Xiaojing Ma, Wei Sheng, Ranran Dai, Zhenglong Guo, Weili Yan, Lili Hao, Guoying Huang, Duan Ma, Bingtao Hao, Jing Ma
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Abstract

Abnormal cardiac development has been observed in individuals with Cornelia de Lange syndrome (CdLS) due to mutations in genes encoding members of the cohesin complex. However, the precise role of cohesin in heart development remains elusive. In this study, we aimed to elucidate the indispensable role of SMC3, a component of the cohesin complex, in cardiac development and its underlying mechanism. Our investigation revealed that CdLS patients with SMC3 mutations have high rates of congenital heart disease (CHD). We utilized heart-specific Smc3-knockout (SMC3-cKO) mice, which exhibit varying degrees of outflow tract (OFT) abnormalities, to further explore this relationship. Additionally, we identified 16 rare SMC3 variants with potential pathogenicity in individuals with isolated CHD. By employing single-nucleus RNA sequencing and chromosome conformation capture high-throughput genome-wide translocation sequencing, we revealed that Smc3 deletion downregulates the expression of key genes, including Ets2, in OFT cardiac muscle cells by specifically decreasing interactions between super-enhancers (SEs) and promoters. Notably, Ets2-SE-null mice also exhibit delayed OFT development in the heart. Our research revealed a novel role for SMC3 in heart development via the regulation of SE-associated genes, suggesting its potential relevance as a CHD-related gene and providing crucial insights into the molecular basis of cardiac development. Understanding heart development is vital as defects in this process are a major cause of birth abnormalities. This study focuses on a protein, SMC3, and its role in heart development. Experiments were conducted on mice genetically altered to lack SMC3 in heart cells. Researchers found that mice without SMC3 had various heart defects, like those seen in humans with congenital heart disease. They also found mutations in the SMC3 gene in patients with congenital heart disease, suggesting a link between SMC3 and heart development in humans. The findings reveal that SMC3 plays a crucial role in heart development, with its absence leading to significant heart defects in mice. These results suggest a potential genetic cause for some forms of congenital heart disease in humans. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author. Introduction

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SMC3 通过调节超级增强子相关基因促进心脏发育。
科尼莉亚-德-朗格综合征(CdLS)患者的心脏发育异常是由于编码凝聚素复合体成员的基因发生突变所致。然而,凝聚素在心脏发育过程中的确切作用仍然难以捉摸。在本研究中,我们旨在阐明凝聚素复合体的一个成分 SMC3 在心脏发育中不可或缺的作用及其内在机制。我们的调查发现,SMC3突变的CdLS患者患有先天性心脏病(CHD)的比例很高。我们利用表现出不同程度流出道(OFT)异常的心脏特异性 Smc3 基因敲除(SMC3-cKO)小鼠来进一步探讨这种关系。此外,我们还发现了 16 个罕见的 SMC3 变体,这些变体在孤立性先天性心脏病患者中具有潜在的致病性。通过采用单核 RNA 测序和染色体构象捕获高通量全基因组易位测序,我们发现 Smc3 缺失会通过特异性减少超级增强子(SE)和启动子之间的相互作用,下调包括 Ets2 在内的关键基因在 OFT 心肌细胞中的表达。值得注意的是,Ets2-SE缺失小鼠也表现出心脏OFT发育延迟。我们的研究揭示了SMC3通过调控SE相关基因在心脏发育过程中的新作用,表明其作为CHD相关基因的潜在相关性,并为了解心脏发育的分子基础提供了重要信息。
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来源期刊
Experimental and Molecular Medicine
Experimental and Molecular Medicine 医学-生化与分子生物学
CiteScore
19.50
自引率
0.80%
发文量
166
审稿时长
3 months
期刊介绍: Experimental & Molecular Medicine (EMM) stands as Korea's pioneering biochemistry journal, established in 1964 and rejuvenated in 1996 as an Open Access, fully peer-reviewed international journal. Dedicated to advancing translational research and showcasing recent breakthroughs in the biomedical realm, EMM invites submissions encompassing genetic, molecular, and cellular studies of human physiology and diseases. Emphasizing the correlation between experimental and translational research and enhanced clinical benefits, the journal actively encourages contributions employing specific molecular tools. Welcoming studies that bridge basic discoveries with clinical relevance, alongside articles demonstrating clear in vivo significance and novelty, Experimental & Molecular Medicine proudly serves as an open-access, online-only repository of cutting-edge medical research.
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