- Browse by Subject
Browsing by Subject "Cardiogenesis"
Now showing 1 - 3 of 3
Results Per Page
Sort Options
Item Genome-wide studies reveal the essential and opposite roles of ARID1A in controlling human cardiogenesis and neurogenesis from pluripotent stem cells(BMC, 2020-07-09) Liu, Juli; Liu, Sheng; Gao, Hongyu; Han, Lei; Chu, Xiaona; Sheng, Yi; Shou, Weinian; Wang, Yue; Liu, Yunlong; Wan, Jun; Yang, Lei; BioHealth Informatics, School of Informatics and ComputingBackground Early human heart and brain development simultaneously occur during embryogenesis. Notably, in human newborns, congenital heart defects strongly associate with neurodevelopmental abnormalities, suggesting a common gene or complex underlying both cardiogenesis and neurogenesis. However, due to lack of in vivo studies, the molecular mechanisms that govern both early human heart and brain development remain elusive. Results Here, we report ARID1A, a DNA-binding subunit of the SWI/SNF epigenetic complex, controls both neurogenesis and cardiogenesis from human embryonic stem cells (hESCs) through distinct mechanisms. Knockout-of-ARID1A (ARID1A−/−) leads to spontaneous differentiation of neural cells together with globally enhanced expression of neurogenic genes in undifferentiated hESCs. Additionally, when compared with WT hESCs, cardiac differentiation from ARID1A −/− hESCs is prominently suppressed, whereas neural differentiation is significantly promoted. Whole genome-wide scRNA-seq, ATAC-seq, and ChIP-seq analyses reveal that ARID1A is required to open chromatin accessibility on promoters of essential cardiogenic genes, and temporally associated with key cardiogenic transcriptional factors T and MEF2C during early cardiac development. However, during early neural development, transcription of most essential neurogenic genes is dependent on ARID1A, which can interact with a known neural restrictive silencer factor REST/NRSF. Conclusions We uncover the opposite roles by ARID1A to govern both early cardiac and neural development from pluripotent stem cells. Global chromatin accessibility on cardiogenic genes is dependent on ARID1A, whereas transcriptional activity of neurogenic genes is under control by ARID1A, possibly through ARID1A-REST/NRSF interaction.Item Identification of putative targets of Nkx2-5 in Xenopus laevis using cross-species annotation and microarray gene expression analysis(2011-10) Breese, Marcus R.; Edenberg, Howard J.; Hurley, Thomas D., 1961-; Rhodes, Simon J.; Skalnik, David GordonThe heart is the first organ to form during development in vertebrates and Nkx2-5 is the first marker of cardiac specification. In Xenopus laevis, Nkx2-5 is essential for heart formation, but early targets of this homeodomain transcription factor have not been fully characterized. In order to discover potential early targets of Nkx2-5, synthetic Nkx2-5 mRNA was injected into eight-cell Xenopus laevis embryos and changes in gene expression measured using microarray analysis. While Xenopus laevis is a commonly used model organism for developmental studies, its genome remains poorly annotated. To compensate for this, a cross-species annotation database called CrossGene was constructed. CrossGene was created by exhaustively comparing UniGene transcripts from Homo sapiens, Mus musculus, Rattus norvegicus, Gallus gallus, Xenopus laevis, Danio rerio, Drosophila melanogaster, and Caenorhabditis elegans using the BLAST family of algorithms. Networks were then assembled by recursively combining reciprocal best matches into groups of orthologous genes. Gene ontology annotation from all organisms could then be applied to all members of the reciprocal group. In this way, the CrossGene database was used to augment the existing genomic annotation of Xenopus laevis. Combining cross-species annotation with differential gene expression analysis of Nkx2-5 overexpression led to the discovery of 99 potential targets of Nkx2-5.Item Single cell evaluation of endocardial Hand2 gene regulatory networks reveals HAND2-dependent pathways that impact cardiac morphogenesis(The Company of Biologists, 2023) George, Rajani M.; Firulli, Beth A.; Podicheti, Ram; Rusch, Douglas B.; Mannion, Brandon J.; Pennacchio, Len A.; Osterwalder, Marco; Firulli, Anthony B.; Pediatrics, School of MedicineThe transcription factor HAND2 plays essential roles during cardiogenesis. Hand2 endocardial deletion (H2CKO) results in tricuspid atresia or double inlet left ventricle with accompanying intraventricular septum defects, hypo-trabeculated ventricles and an increased density of coronary lumens. To understand the regulatory mechanisms of these phenotypes, single cell transcriptome analysis of mouse E11.5 H2CKO hearts was performed revealing a number of disrupted endocardial regulatory pathways. Using HAND2 DNA occupancy data, we identify several HAND2-dependent enhancers, including two endothelial enhancers for the shear-stress master regulator KLF2. A 1.8 kb enhancer located 50 kb upstream of the Klf2 TSS imparts specific endothelial/endocardial expression within the vasculature and endocardium. This enhancer is HAND2-dependent for ventricular endocardium expression but HAND2-independent for Klf2 vascular and valve expression. Deletion of this Klf2 enhancer results in reduced Klf2 expression within ventricular endocardium. These data reveal that HAND2 functions within endocardial gene regulatory networks including shear-stress response.