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Elevated microRNA-187 causes cardiac endothelial dysplasia to promote congenital heart disease through inhibition of NIPBL [ATAC-Seq]

ABSTRACT: Dysplasia of cardiac endothelial cells significantly contributes to congenital heart disease (CHD), the most common congenital disability. The regulatory role of miRNAs in this process remains elusive. This study identified elevated miR-187 expression in embryonic heart endothelial cells from CHD fetuses. Using a conditional knock-in model, we showed that increased miR-187 levels in embryonic endothelial cells induce CHD in homozygous fetal mice, closely mirroring human CHD. Mechanistically, miR-187 targets NIPBL, which is responsible for recruiting the cohesin complex and facilitating chromatin accessibility between enhancers and promoters. Consequently, the endothelial cell-specific upregulation of miR-187 inhibited NIPBL, leading to reduced chromatin accessibility and impaired gene expression, which hindered endothelial cell development and ultimately caused heart septal defects and reduced heart size both in vitro and in vivo. Importantly, exogenous miR-187 expression in human cardiac organoids mimicked developmental defects in the cardiac endothelial cells, reversible by NIPBL replenishment. Our findings establish the miR-187/NIPBL axis as a potent regulator that inhibits cardiac endothelial cell development by attenuating the transcription of numerous endothelial genes, with our mouse and human cardiac organoid models effectively replicating severe defects from minor perturbations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276221 | GEO | 2024/11/03

REPOSITORIES: GEO

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Elevated microRNA-187 causes cardiac endothelial dysplasia to promote congenital heart disease through inhibition of NIPBL

Project description:Dysplasia of cardiac endothelial cells significantly contributes to congenital heart disease (CHD), the most common congenital disability. The regulatory role of miRNAs in this process remains elusive. This study identified elevated miR-187 expression in embryonic heart endothelial cells from CHD fetuses. Using a conditional knock-in model, we showed that increased miR-187 levels in embryonic endothelial cells induce CHD in homozygous fetal mice, closely mirroring human CHD. Mechanistically, miR-187 targets NIPBL, which is responsible for recruiting the cohesin complex and facilitating chromatin accessibility between enhancers and promoters. Consequently, the endothelial cell-specific upregulation of miR-187 inhibited NIPBL, leading to reduced chromatin accessibility and impaired gene expression, which hindered endothelial cell development and ultimately caused heart septal defects and reduced heart size both in vitro and in vivo. Importantly, exogenous miR-187 expression in human cardiac organoids mimicked developmental defects in the cardiac endothelial cells, reversible by NIPBL replenishment. Our findings establish the miR-187/NIPBL axis as a potent regulator that inhibits cardiac endothelial cell development by attenuating the transcription of numerous endothelial genes, with our mouse and human cardiac organoid models effectively replicating severe defects from minor perturbations.

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Nono deficiency impedes the proliferation and adhesion of H9c2 cardiomyocytes through Pi3k/Akt signaling pathway [ATAC-seq]

Project description:Purpose: Congenital heart disease (CHD) is the most common type of birth defect and the main noninfectious cause of death during the neonatal stage. Currently, hemizygous loss-of-function variants in NONO(The non-POU domain containing, octamer-binding) gene have been described as the cause of congenital heart defects in males. However, the effects of NONO on cardiac development have not been fully elucidated.

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Hif1α down-regulation is associated with transposition of great arteries in mice treated with a RA antagonist

Project description:Aims: Congenital heart defect (CHD) account for 25% of all human congenital abnormalities. Very few CHD-causing genes have been identified so far; so, to discover further genes we performed a global transcriptome analysis in mouse models of CHD. Methods and results: By the use of a retinoic acid competitive antagonist (BMS-189453) we caused CHD, thymic abnormalities and neural tube defects in mouse newborns. Transposition of great arteries was the prevalent cardiac defect observed (61%). Recently we were able to partially rescue this abnormal phenotype by oral administration of folic acid. Now we have performed a microarray analysis in mouse embryos (8.5 dpc) treated with BMS-189453 alone and with BMS-189453 plus folic acid (FA). On the basis of microarray and QRT-PCR results, we deeper analysed Hif1α because of its down-regulation in BMS-treated embryos vs WT and its increased expression level in BMS+FA treated embryos compared to BMS-treated ones. Immunofluorescence experiments confirmed the under-expression of Hif1α protein in BMS-treated embryos compared to WT and BMS+FA treated ones and moreover demonstrated that at 8.5 dpc Hif1α is mainly expressed in the embryo’s heart. Conclusion: We propose that Hif1α down-regulation by blocking retinoic acid binding, may contribute to the development of the cardiac defects of mouse newborns. In line with our hypothesis, when Hif1α expression level is restored (by supplementation of folic acid) a decrement of CHD is found. At the best of our knowledge this is the first report that link retinoic acid metabolism to Hif1α regulation and the development of TGA 2 samples w/ 2 dye-swaps

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Project description:Congenital Heart Disease (CHD) accounts for 1% of birth defects, and while large-scale genetic studies have uncovered genes associated with CHDs, identifying causal mutations remains a challenge. We hypothesized that genetic determinants for CHDs could be found in the protein interactomes of GATA4 and TBX5, two cardiac transcription factors (TFs) associated with CHDs. Defining their interactomes in human cardiac progenitors via affinity purification-mass spectrometry and integrating the results with genetic data from the Pediatric Cardiac Genomic Consortium (PCGC) revealed an enrichment of de novo variants among proteins that interact with GATA4 or TBX5. A consolidative score designed to prioritize TF interactome members based on distinctive variant, gene and proband features identified numerous likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied cardiac developmental genes resulting in co-activation and the GLYR1 variant associated with CHD disrupted interaction with GATA4. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating the contribution of genetic variants in CHD and can be extended to other genetic diseases.

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Systems analysis of de novo mutations in congenital heart diseases identified a protein network in the hypoplastic left heart syndrome

Project description:Congenital heart diseases (CHD) are a class of birth defects affecting ~1% of live births. These conditions are hallmarked by extreme genetic heterogeneity, and therefore, despite a strong genetic component, only a very handful of at-risk loci in CHD have been identified. We herein introduced systems analyses to uncover the hidden organization on biological networks of genomic mutations in CHD, and leveraged network analysis techniques to integrate the human interactome, large-scale patient exomes, the fetal heart spatial transcriptomes, and single-cell transcriptomes of clinical samples. We identified a highly connected network in CHD where most of the member proteins had previously uncharacterized functions in regulating fetal heart development. While genes on the network displayed strong enrichment for heart-specific functions, a sub-group, active specifically at early developmental stages, also regulates fetal brain development, thereby providing mechanistic insights into the clinical comorbidities between CHD and neurodevelopmental conditions. At a small scale, we experimentally verified previously uncharacterized cardiac functions of several novel proteins employing cellular assays and gene editing techniques. At a global scale, our study revealed developmental dynamics of the identified CHD network and observed the strongest enrichment for pathogenic mutations in the network specific to hypoplastic left heart syndrome (HLHS). Our single-cell transcriptome analysis further identified pervasive dysregulation of the network in cardiac endothelial cells and the conduction system in the HLHS left ventricle. Taken together, our systems analyses identified novel factors in CHD, revealed key molecular mechanisms in HLHS, and provides a generalizable framework readily applicable to studying many other complex diseases.

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