The role of SMC3 in heart development by regulating super-enhancer associated genes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1015646 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26041600_1.fastq.gz | Fastqsanger.gz | |||
| SRR26041600_2.fastq.gz | Fastqsanger.gz | |||
| SRR26041601_1.fastq.gz | Fastqsanger.gz | |||
| SRR26041601_2.fastq.gz | Fastqsanger.gz | |||
| SRR26041602_1.fastq.gz | Fastqsanger.gz |
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Project description: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. But 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 an association between SMC3 mutations and congenital heart disease (CHD) in CdLS patients. To further explore this relationship, we utilized heart-specific Smc3-knockout (SMC3-cKO) mice, which displayed varying degrees of outflow tract (OFT) abnormalities. Additionally, we identified 16 rare SMC3 variants with potential pathogenicity in individuals with isolated CHD. Employing single nucleus RNA sequencing and 3C-high-throughput genome-wide translocation sequencing, we unveiled that Smc3 deletion downregulates the expression of key genes, including Ets2, in OFT cardiac muscle cells by specifically decreasing interactions between super-enhancers (SE) and promoters. Notable, Ets2-SE-null mice also exhibit delayed OFT development in the heart. Our research uncovers a novel role for SMC3 in heart development by regulating SE-associated genes, suggesting its potential relevance as one of the CHD-related genes and providing crucial insights into the molecular basis of cardiac development.
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Project description: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.
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Project description:Many genes determining cell identity are regulated by a set of enhancer elements collectively referred to as super-enhancers. It has been suggested that super-enhancers represent a new class of cis-element, in which the assembly of enhancers confers an emergent property from the extended regulatory domain. To investigate this, we used published criteria to define one of the strongest super-enhancers in mouse erythroid cells – a 24kb region regulating α-globin expression, which comprises five enhancer-like components. Using homologous recombination, we deleted each component of this super-enhancer, singly and in informative combinations, and examined hematologic phenotype, gene expression, chromatin structure and chromosome conformation. Each component behaves independently, in an additive rather than synergistic manner. We conclude that the sub-classification of enhancers is unjustified beyond a description of their strength, which is defined by the number of lineage-specific transcription factors they bind. These findings ask afresh why enhancer-like elements cluster at key genes.
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