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Spatiotemporal Gene Coexpression and Regulation in Mouse Cardiomyocytes of Early Cardiac Morphogenesis.

ABSTRACT: Background Heart tube looping to form a 4-chambered heart is a critical stage of embryonic heart development, but the gene drivers and their regulatory targets have not been extensively characterized at the cell-type level. Methods and Results To study the interaction of signaling pathways, transcription factors (TFs), and genetic networks in the process, we constructed gene co-expression networks and identified gene modules highly activated in individual cardiomyocytes at multiple anatomical regions and developmental stages using previously published single-cell RNA-seq data. Function analyses of the modules uncovered major pathways important for spatiotemporal cardiomyocyte differentiation. Interestingly, about half of the pathways were highly active in cardiomyocytes at the outflow tract (OFT) and atrioventricular canal, including well-known pathways for cardiac development and many newly identified ones. We predicted that these OFT-atrioventricular canal pathways were regulated by a large number of TFs actively expressed at the OFT-atrioventricular canal cardiomyocytes, with the prediction supported by motif enrichment analysis, including 10 TFs that have not been previously associated with cardiac development (eg, Etv5, Rbpms, and Baz2b). Furthermore, we found that TF targets in the OFT-atrioventricular canal modules were most significantly enriched with genes associated with mouse heart developmental abnormalities and human congenital heart defects, in comparison with TF targets in other modules, consistent with the critical developmental roles of OFT. Conclusions By analyzing gene co-expression at single cardiomyocytes, our systematic study has uncovered many known and additional new important TFs and their regulated molecular signaling pathways that are spatiotemporally active during heart looping.

SUBMITTER: Liu Y

PROVIDER: S-EPMC6761639 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Spatiotemporal Gene Coexpression and Regulation in Mouse Cardiomyocytes of Early Cardiac Morphogenesis.

Liu Yang Y Lu Pengfei P Wang Yidong Y Morrow Bernice E BE Zhou Bin B Zheng Deyou D

Journal of the American Heart Association 20190719 15

Background Heart tube looping to form a 4-chambered heart is a critical stage of embryonic heart development, but the gene drivers and their regulatory targets have not been extensively characterized at the cell-type level. Methods and Results To study the interaction of signaling pathways, transcription factors (TFs), and genetic networks in the process, we constructed gene co-expression networks and identified gene modules highly activated in individual cardiomyocytes at multiple anatomical re ...[more]

PMID: 31322043

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Project description:Background Cardiac hypertrophy may be classified as either physiological or pathological. Pathological hypertrophy has a complex etiology and is genetically regulated. In this study, we used a mouse model of cardiac hypertrophy to explore the mechanisms of gene regulation, in particular, modulation of the expression of target genes through transcription factor activity, regulation of immune and inflammation-associated genes and regulation of the alternative splicing of transcription factors. Methods Mouse models of pathological cardiac hypertrophy were established by transverse aortic constriction (TAC). We overexpressed HSPA1A in mouse cardiac HL-1 cells. GO and KEGG pathway annotation database was used to analyze all DEGs. Results The expression of HSPA1A differed significantly between TAC + dantrolene vs. sham + dantrolene (Sham was the non-TAC group, and DMSO was the contrast agent), and TAC + DMSO vs. sham + DMSO. The RNA-binding protein Zfp36 was found to be differentially expressed between both TAC + dantrolene vs. sham + dantrolene and TAC + DMSO vs. sham + DMSO. The expression of mki67 and gm5619 was significantly different between TAC + dantrolene and TAC + DMSO. HSPA1A was found to selectively regulate the expression of non-coding RNAs related to cardiac hypertrophy, including Rn7sk and RMRP. The downregulated genes were mainly related to inflammation and the immune response. HSPA1A negatively regulated alternative splicing of Asxl2 and positively regulated alternative splicing of Runx1. Conclusions HSPA1A was closely related to cardiac hypertrophy. Zfp36 was also related to cardiac hypertrophy. Dantrolene may delay cardiac hypertrophy and ventricular remodeling by regulating the expression of the RNA-binding protein genes mki67 and gm5619. HSPA1A positively regulated the expression of the non-coding RNAs RN7SK and RMRP while negatively regulating the expression of inflammation- and immune response-related genes. HSPA1A can play a role in cardiac hypertrophy by regulating the alternative splicing of asxl2 and runx1.

Dataset Information

Spatiotemporal Gene Coexpression and Regulation in Mouse Cardiomyocytes of Early Cardiac Morphogenesis.

Publications

Spatiotemporal Gene Coexpression and Regulation in Mouse Cardiomyocytes of Early Cardiac Morphogenesis.

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