SMC3通过调节超级增强子相关基因促进心脏发育-动脉网

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

Nature 等信源发布 2024-08-01 09:58

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AbstractAbnormal 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.

摘要由于编码粘着蛋白复合物成员的基因突变，在患有Cornelia de Lange综合征（CdLS）的个体中观察到异常的心脏发育。然而，粘着蛋白在心脏发育中的确切作用仍然难以捉摸。在这项研究中，我们旨在阐明粘着蛋白复合物的组成部分SMC3在心脏发育中不可或缺的作用及其潜在机制。

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.

我们的调查显示，具有SMC3突变的CdLS患者先天性心脏病（CHD）的发生率很高。我们利用表现出不同程度的流出道（OFT）异常的心脏特异性Smc3基因敲除（Smc3 cKO）小鼠来进一步探索这种关系。此外，我们确定了16种罕见的SMC3变异体，这些变异体在孤立的冠心病患者中具有潜在的致病性。

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.

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缺失通过特异性降低超增强子（SE）和启动子之间的相互作用来下调OFT心肌细胞中关键基因（包括Ets2）的表达。

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..

。我们的研究揭示了SMC3通过调控SE相关基因在心脏发育中的新作用，表明其作为冠心病相关基因的潜在相关性，并为心脏发育的分子基础提供了重要见解。。

Congenital heart disease (CHD) is the most common congenital anomaly in newborns, affecting 8-12/1000 live births worldwide and accounting for approximately 40% of prenatal deaths1. CHD arises from abnormal heart development during the embryonic stage and has a strong heritable component. Cardiogenesis is a precise and tightly controlled process involving outflow tract (OFT) formation, the development of four cardiac chambers, and the specialization of cardiac muscle cells2.

先天性心脏病（CHD）是新生儿中最常见的先天性异常，影响全球8-12/1000活产，约占产前死亡的40%1。冠心病是由胚胎期心脏发育异常引起的，具有很强的遗传成分。心脏发生是一个精确且严格控制的过程，涉及流出道（OFT）的形成，四个心室的发育以及心肌细胞的特化2。

Many signaling pathways and tissue-specific transcriptional regulators contribute to the regulation of heart development. Dysregulation of the dynamic control of these specific biological processes may lead to CHD. For instance, the Notch pathway plays a crucial role in early OFT formation by arresting proliferation and promoting the differentiation of second heart field progenitors3, and defects in this pathway lead to various CHD phenotypes4.Super-enhancers (SEs) are a class of regulatory regions comprising clusters of enhancers densely occupied by master regulators and mediators5.

许多信号通路和组织特异性转录调节因子有助于调节心脏发育。这些特定生物过程的动态控制失调可能导致冠心病。例如，Notch途径通过阻止增殖和促进第二心脏场祖细胞的分化在早期OFT形成中起着至关重要的作用3，并且该途径中的缺陷导致各种CHD表型4。超增强子（SE）是一类调控区域，包括由主调节因子和介体密集占据的增强子簇5。

SEs exert powerful transcriptional activation effects on genes that are crucial for cell identity6. Previous evidence suggested that SEs play a significant role in the genetic control network of the heart7,8,9. For example, TGF-β-mediated binding of the chromatin reader protein BRD4 to SEs can promote the expression of genes involved in cardiac fibroblast activation8.

SE对细胞鉴定至关重要的基因发挥强大的转录激活作用6。先前的证据表明，SEs在心脏的遗传控制网络中起着重要作用7,8,9。例如，TGF-β介导的染色质读取器蛋白BRD4与SE的结合可以促进参与心脏成纤维细胞活化的基因的表达8。

A conserved SE controls the expression of Nppa and Nppb in heart development and homeostasis. Deletion of this SE results in manifestations similar to those in Nppa-Nppb knockout mice, indicating the physiological importance of this SE in cardiac disease9. Although a study analyzing a large database generated a comprehensive catalog of SEs in 86 human cell.

保守的SE控制心脏发育和体内平衡中Nppa和Nppb的表达。这种SE的缺失导致类似于Nppa-Nppb基因敲除小鼠的表现，表明这种SE在心脏病中的生理重要性9。尽管一项分析大型数据库的研究生成了86个人类细胞中SE的综合目录。

SMC3 variants are identified in patients with isolated congenital heart diseaseDe novo mutations in SMC3 contribute to approximately 1–2% of CdLS-like phenotypes, with a significant proportion displaying noncanonical CdLS phenotypes14. Upon examination of the CHD type of CdLS individuals26,27,28,29,30,31 with SMC3 mutations, we found that a majority (76.2% or 16 out of 21) exhibited aorta and pulmonary artery dysplasia, consistent with the phenotypes of SMC3-cKO mice (Fig.

在孤立的先天性心脏病患者中发现了SMC3变异SMC3的从头突变约占CdLS样表型的1-2%，其中很大一部分表现出非典型CdLS表型14。通过检查具有SMC3突变的CHD型CdLS个体26,27,28,29,30,31，我们发现大多数（76.2%或21个中的16个）表现出主动脉和肺动脉发育不良，与SMC3 cKO小鼠的表型一致（图）。

2a). We extracted DNA samples for Sanger sequencing from 56 individuals with isolated CHD, including those with TOF and VSD, corresponding to the heart defects observed in SMC3-cKO mice, to understand the relevance of SMC3 variants in CHD patients without a distinct CdLS phenotype. Two candidate pathogenic variants (R221T and T857S) in the coding region were identified in two TOF patients based on the following filtering criteria: 1) excluding synonymous variants; 2) variants with a minor allele frequency (MAF) less than 0.1% according to the public control database; and 3) the variant type was a nonsense, frameshift or missense variant predicted to be deleterious by at least two algorithms (Fig.

2a）。我们从56名孤立的CHD患者（包括TOF和VSD患者）中提取了DNA样本进行Sanger测序，这些样本对应于在SMC3 cKO小鼠中观察到的心脏缺陷，以了解SMC3变异在没有明显CdLS表型的CHD患者中的相关性。根据以下过滤标准，在两名TOF患者中鉴定出编码区的两个候选致病变体（R221T和T857S）：1）排除同义变体；2）根据公共控制数据库，次要等位基因频率（MAF）小于0.1%的变体；3）变体类型是至少两种算法预测有害的无意义，移码或错义变体（图）。

2b, c, Supplementary Table 3). Subsequently, through multiplex PCR-targeting sequencing, we searched for SMC3 variants in a larger cohort of 1083 patients with isolated CHD from our previous study20 and found one candidate pathogenic variant (Y434C) in the coding region from a patient with TOF after filtering using the same criteria.

2b，c，补充表3）。随后，通过多重PCR靶向测序，我们从先前的研究中搜索了1083例孤立性CHD患者的较大队列中的SMC3变体20，并在使用相同标准过滤后，在TOF患者的编码区中发现了一种候选致病变体（Y434C）。

We also detected six variants with potential pathogenicity in the noncoding region from patients with VSD or TOF according to a MAF less than 0.1%, and these variants are predicted to affect SMC3 expression (located on regulatory DNA elements, affect the consensus splice site, or.

根据MAF小于0.1%，我们还从VSD或TOF患者的非编码区检测到六个具有潜在致病性的变体，预计这些变体会影响SMC3的表达（位于调节性DNA元件上，影响共有剪接位点，或。

Data availability

数据可用性

The data that support the findings of this study are available from the corresponding author upon reasonable request. All the raw high-throughput sequence data are available in the GEO (GSE242974). All research materials listed in the Methods section are also included in the major resources table (Supplementary Table 1).

根据合理的要求，通讯作者可以提供支持本研究结果的数据。GEO（GSE242974）中提供了所有原始高通量序列数据。方法部分列出的所有研究材料也包含在主要资源表（补充表1）中。

The ChIP-seq data were downloaded from the GEO database and are displayed in Supplementary Table 1..

ChIP-seq数据是从GEO数据库下载的，并显示在补充表1中。。

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Download referencesAcknowledgementsWe thank the patients who participated in this study. We thank Professor Yujiang Geno Shi from Fudan University for providing excellent guidance on writing the article and Professor Jikui Wang from Xinxiang Medical University for providing substantial support in diagnosing the cardiac phenotypes of mice.

下载参考文献致谢我们感谢参与本研究的患者。我们感谢复旦大学的于江·吉诺·施教授为撰写本文提供了出色的指导，并感谢新乡医科大学的王季奎教授为诊断小鼠心脏表型提供了实质性支持。

We also thank our peers for providing the WES data from patients with isolated CHD. This work was supported by the National Key Research and Development Program of China (2021YFC2701001 to D.M.), the National Natural Science Foundation of China (No. 82271889 to J.M., 31970836 to B.H., and 32170885 to B.H.), and the National Science Foundation for Young Scientists (No.

我们还感谢同行提供了孤立性冠心病患者的WES数据。这项工作得到了中国国家重点研究与发展计划（2021YFC2701001至D.M.），国家自然科学基金（J.M.第82271889号，B.H.第31970836号和B.H.第32170885号）和国家青年科学基金（No。

81801501 to J.M.).Author informationAuthor notesThese authors contributed equally: Bowen Zhang, Yongchang Zhu.Authors and AffiliationsKey Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences; ENT Institute, Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital; Institute of Medical Genetics & Genomics; Key Laboratory of Birth Defects, Children’s Hospital; Medical Science Data Center at Intelligent Medicine Institute, Fudan University, Shanghai, 200032, ChinaBowen Zhang, Feizhen Wu, Xiaojing Ma, Wei Sheng, Weili Yan, Lili Hao, Guoying Huang, Duan Ma & Jing MaHenan Medical Genetics Institute, Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, People’s Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, ChinaYongchang Zhu & Zhenglong GuoShanghai Pediatric Congenital Heart Disease Institute and Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, Shanghai Jiao Ton.

81801501至J.M.）。作者信息作者注意到这些作者做出了同样的贡献：张博文，朱永昌。作者和附属机构教育部代谢与分子医学实验室，基础医学院生物化学与分子生物学系；耳鼻喉科医院面部整形与重建外科耳鼻喉科研究所；医学遗传学与基因组学研究所；儿童医院出生缺陷重点实验室；复旦大学智能医学研究所医学科学数据中心，上海，200032，张博文，吴飞珍，马晓静，魏胜，严伟丽，郝丽丽，黄国英，段马和马海南医学遗传学研究所，河南省遗传病和功能基因组学重点实验室，郑州大学郑州人民医院，郑州，450000，中国朱永昌和郑龙，国上海儿童先天性心脏病研究所和儿童转化医学研究所，上海儿童医学中心，上海蛟顿。

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Reprints and permissionsAbout this articleCite this articleZhang, B., Zhu, Y., Zhang, Z. et al. SMC3 contributes to heart development by regulating super-enhancer associated genes.

转载和许可本文引用本文Zhang，B.，Zhu，Y.，Zhang，Z。等人。SMC3通过调节超增强子相关基因促进心脏发育。

Exp Mol Med (2024). https://doi.org/10.1038/s12276-024-01293-0Download citationReceived: 29 September 2023Revised: 23 April 2024Accepted: 21 May 2024Published: 01 August 2024DOI: https://doi.org/10.1038/s12276-024-01293-0Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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