Single-Cell Transcriptome Analysis Maps the Developmental Track of the Human Heart

Cui, Yueli; Zheng, Yuxuan; Liu, Xixi; Yan, Liying; Fan, Xiaoying; Yong, Jun; Hu, Yuqiong; Dong, Ji; Li, Qingqing; Wu, Xinglong; Gao, Shuai; Li, Jingyun; Wen, Lu; Qiao, Jie; Tang, Fuchou

doi:10.1016/j.celrep.2019.01.079

Cited by 354 publications

(392 citation statements)

References 69 publications

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“…Here, we explored the published scRNA-seq datasets from various tissues and organs of different human body systems, including the respiratory system [4,5] (nasal mucosa, respiratory track, bronchus, and lung), the cardiovascular system [6] (heart), the digestive system [7][8][9][10] (esophagus, stomach, ileum, and liver), and the urinary system [11,12] (kidney and bladder). The lung scRNA-seq data were acquired from the Gene Expression Omnibus (GEO) database under the series number GSE122960; the nasal mucosa, respiratory track, bronchus scRNA-seq data were from GSE121600; the heart data were from GSE106118; the esophagus data were downloaded from https://www.tissuestabilitycellatlas.org/; the ileum data were from GSE134809 sample GSM3972018; the stomach data were from GSE134520 sample GSM3954949; the liver data were from GSE115469; the kidney data were from GSE109564; and the bladder data were from GSE129845 sample GSM3723358.…”

Section: Methodsmentioning

confidence: 99%

Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection

et al. 2020

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It has been known that, the novel coronavirus, 2019-nCoV, which is considered similar to SARS-CoV and originated from Wuhan (China), invades human cells via the receptor angiotensin converting enzyme II (ACE2). Moreover, lung cells that have ACE2 expression may be the main target cells during 2019-nCoV infection. However, some patients also exhibit non-respiratory symptoms, such as kidney failure, implying that 2019-nCoV could also invade other organs. To construct a risk map of different human organs, we analyzed the single-cell RNA sequencing (scRNA-seq) datasets derived from major human physiological systems, including the respiratory, cardiovascular, digestive, and urinary systems. Through scRNA-seq data analyses, we identified the organs at risk, such as lung, heart, esophagus, kidney, bladder, and ileum, and located specific cell types (i.e., type II alveolar cells (AT2), myocardial cells, proximal tubule cells of the kidney, ileum and esophagus epithelial cells, and bladder urothelial cells), which are vulnerable to 2019-nCoV infection. Based on the findings, we constructed a risk map indicating the vulnerability of different organs to 2019-nCoV infection. This study may provide potential clues for further investigation of the pathogenesis and route of 2019-nCoV infection.

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Section: Methodsmentioning

confidence: 99%

Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection

et al. 2020

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“…[15] And another dataset of human placenta can be download by the Gene Expression Omnibus GSE89497 (corresponding to Figure 1C). [16] Human fetal Heart: Gene expression matrix of scRNA-seq data of human fetal heart was downloaded from the Gene Expression Omnibus (GSE106118) and the annotation was downloaded from the supplementary table1 from the Cui, et al (2019). [17] Human fetal liver: Gene expression matrix of scRNA-seq data of human fetal liver was downloaded from ArrayExpress with accession code E-MTAB-7407 and the annotation was downloaded the supplementary table from Popescu, et al(2019).…”

Section: Public Dataset Acquisition and Processingmentioning

confidence: 99%

“…We then screened the ACE2 expression in multiple fetal organs including heart, lungs, liver and kidneys based on the online published single cell transcriptome studies. In a fetal heart single cell study covering early to late fetal stages [17], we observed that ACE2 was expressed in cardiomyocytes (CM), macrophages and smooth muscle cells and pericytes (SMC/Peri). In a human feral liver cell atlas [18], ACE2 was detected in erythroid, fibroblast and hepatocyte ( Figure 2B).…”

Section: Cell Specific Expression Of Ace2 In Human Fetal Organsmentioning

confidence: 99%

The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single cell transcriptome study

Chen

Xiong

et al. 2020

Preprint

130

144

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Recent studies have demonstrated that SARS-CoV-2 cell entry depends on both ACE2 and TMPRSS2 genes (DOI: 10.1016/j.cell.2020.02.052), but our current work only focus on ACE2, which is insufficient to support the conclusion of this paper. So the authors have withdrawn their manuscript whilst they perform additional experiments and analysis to test some of their conclusions further. Therefore, the authors do not wish this work to be cited as reference for the project.

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“…The following prediction software was used to analyze the rare variants in candidate CHD genes identified through WES: SIFT, GERP++, Polyphen2 Complex, Polyphen2 Mendelian, MetaSVM, MetaLR, and CADD [27][28][29][30][31][32]. Variants were further filtered based on the expression of the impacted human gene in the developing heart using publicly available single-cell data [70]. MYL2 genomic region flanking the identified variant was amplified using MYL2.gen.For and MYL2.gen.Rev primers and the presence of the variant was confirmed using Sanger sequencing method.…”

Section: Variant Identification Prioritization and Confirmationmentioning

confidence: 99%

Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy

Manivannan

Darouich

Masmoudi

et al. 2019

Preprint

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Hypertrophic cardiomyopathy (HCM) is characterized by enlargement of the ventricular muscle without dilation and is often associated with dominant pathogenic variants in cardiac sarcomeric protein genes. Here, we report a family with two infants diagnosed with infantile-onset HCM and mitral valve dysplasia that led to death before one year of age. Using exome sequencing, we discovered that one of the affected children had a homozygous frameshift variant in Myosin light chain 2 (MYL2:NM_000432.3:c.431_432delCT: p.Pro144Argfs*57;MYL2-fs), which alters the last 20 amino acids of the protein and is predicted to impact the C-terminal EF-hand (CEF) domain. The parents are unaffected heterozygous carriers of the variant and the variant is absent in control cohorts from gnomAD. The absence of the phenotype in carriers and infantile presentation of severe HCM is in contrast to HCM associated with dominant MYL2 variants. Immunohistochemical analysis of the ventricular muscle of the deceased patient with the MYL2fs variant showed marked reduction of MYL2 expression compared to an unaffected control. In vitro overexpression studies further indicate that the MYL2-fs variant is actively degraded. In contrast, an HCM-associated missense variant (MYL2:p.Gly162Arg) and three other MYL2 stopgain variants that lead to loss of the CEF domain are stably expressed. However, stopgain variants show impaired localization suggesting a functional role for the CEF domain. The degradation of the MYL2-fs can be rescued by inhibiting the cell's proteasome function supporting a post-translational effect of the variant. In vivo rescue experiments with a Drosophila MYL2homolog (Mlc2) knockdown model indicate that neither MYL2-fs nor MYL2:p.Gly162Argsupports regular cardiac function. The tools that we have generated provide a rapid screening platform for functional assessment of variants of unknown significance in MYL2. Our study 3 supports an autosomal recessive model of inheritance for MYL2 loss-of-function variants and highlights the variant-specific molecular differences found in MYL2-associated cardiomyopathies. Author SummaryWe report a novel frameshift variant in MYL2 that is associated with a severe form of infantile-onset hypertrophic cardiomyopathy. The impact of the variant is only observed in the recessive form of the disease in the proband and not in the parents who are carriers of the variant. This is in contrast to other dominant variants in MYL2 that are associated with cardiomyopathies.We compared the stability of this variant to that of other cardiomyopathy associated MYL2 variants and found molecular differences in the disease pathology. We also show different protein domain requirement for stability and localization of MYL2 in cardiomyocytes. Further, we used a fly model to demonstrate functional deficits due to the variant in the developing heart. Overall, our study shows a molecular mechanism by which loss-of-function variants in MYL2 are recessive while missense variants are dominant. We highlight the use of exome sequencing...

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Single-Cell Transcriptome Analysis Maps the Developmental Track of the Human Heart

Cited by 354 publications

References 69 publications

Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection

Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection

The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single cell transcriptome study

Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy

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