Similar Datasets
Project description:The transcription factor MEF2C plays a critical role in the development of the linear heart tube, but the specific transcriptional networks controlled by MEF2C remain largely undefined. To address this, we performed combined single-nucleus RNA- and ATAC- sequencing on wild type and MEF2C-null embryos at distinct stages of development. We identified a broadly “posteriorized” cardiac gene signature and chromatin landscape throughout the heart tube in the absence of MEF2C. By integrating our gene expression and chromatin accessibility data in a deep-learning based model, we were able to construct developmental trajectories for each of the outflow tract, ventricular, and inflow tract lineages and determined how each of these segment-specific trajectories were distinctly altered in the MEF2C-null embryos. We computationally identified potential segment-specific MEF2C-dependent enhancers. Using transgenesis in zebrafish embryos, we identified novel MEF2C-dependent enhancers with activity in the developing heart tube from among these candidates. Finally, using inferred gene regulatory networks we discovered a genetic interaction between MEF2C and the atrial nuclear hormone receptor NR2F2, revealing that the MEF2C-null heart malformations are partly driven by a transcriptional network with increased NR2F2 activity. These studies not only provide a rich description of the genomic regulation of early heart tube development, but provide a generalizable framework for using genetic mutants to dissect the transcriptional networks that govern developmental processes.
2024-11-04 | GSE280543 | GEO
Project description:The transcription factor MEF2C plays a critical role in the development of the linear heart tube, but the specific transcriptional networks controlled by MEF2C remain largely undefined. To address this, we performed combined single-nucleus RNA- and ATAC- sequencing on wild type and MEF2C-null embryos at distinct stages of development. We identified a broadly “posteriorized” cardiac gene signature and chromatin landscape throughout the heart tube in the absence of MEF2C. By integrating our gene expression and chromatin accessibility data in a deep-learning based model, we were able to construct developmental trajectories for each of the outflow tract, ventricular, and inflow tract lineages and determined how each of these segment-specific trajectories were distinctly altered in the MEF2C-null embryos. We computationally identified potential segment-specific MEF2C-dependent enhancers. Using transgenesis in zebrafish embryos, we identified novel MEF2C-dependent enhancers with activity in the developing heart tube from among these candidates. Finally, using inferred gene regulatory networks we discovered a genetic interaction between MEF2C and the atrial nuclear hormone receptor NR2F2, revealing that the MEF2C-null heart malformations are partly driven by a transcriptional network with increased NR2F2 activity. These studies not only provide a rich description of the genomic regulation of early heart tube development, but provide a generalizable framework for using genetic mutants to dissect the transcriptional networks that govern developmental processes.
2024-11-04 | GSE280538 | GEO
Project description:Heart tube morphogenesis is regulated by segment-specific gene regulatory networks controlled by MEF2C
| PRJNA1179451 | ENA
Project description:Heart tube morphogenesis is regulated by segment-specific gene regulatory networks controlled by MEF2C [snATAC-seq]
| PRJNA1179365 | ENA
Project description:Heart tube morphogenesis is regulated by segment-specific gene regulatory networks controlled by MEF2C [snRNA-Seq]
| PRJNA1179369 | ENA
Project description:During embryogenesis the heart forms as a linear tube that then undergoes multiple simultaneous morphogenetic events to obtain its mature shape. To understand the gene regulatory networks (GRNs) driving this phase of heart development, during which many congenital heart disease malformations likely arise, we conducted an RNA-seq timecourse in zebrafish from 30?hpf to 72?hpf and identified 5861 genes with altered expression. We clustered the genes by temporal expression pattern, identified transcription factor binding motifs enriched in each cluster, and generated a model GRN for the major gene batteries in heart morphogenesis. This approach predicted hundreds of regulatory interactions and found batteries enriched in specific cell and tissue types, indicating that the approach can be used to narrow the search for novel genetic markers and regulatory interactions. Subsequent analyses confirmed the GRN using two mutants, Tbx5 and nkx2-5, and identified sets of duplicated zebrafish genes that do not show temporal subfunctionalization. This dataset provides an essential resource for future studies on the genetic/epigenetic pathways implicated in congenital heart defects and the mechanisms of cardiac transcriptional regulation.
| S-EPMC5665485 | biostudies-literature
Project description:BACKGROUND: The genetic cascades underpinning vertebrate early eye morphogenesis are poorly understood. One gene family essential for eye morphogenesis encodes the retinal homeobox (Rx) transcription factors. Mutations in the human retinal homeobox gene (RAX) can lead to gross morphological phenotypes ranging from microphthalmia to anophthalmia. Zebrafish rx3 null mutants produce a similar striking eyeless phenotype with an associated expanded forebrain. Thus, we used zebrafish rx3-/- mutants as a model to uncover an Rx3-regulated gene network during early eye morphogenesis. RESULTS: Rx3-regulated genes were identified using whole transcriptomic sequencing (RNA-seq) of rx3-/- mutants and morphologically wild-type siblings during optic vesicle morphogenesis. A gene co-expression network was then constructed for the Rx3-regulated genes, identifying gene cross-talk during early eye development. Genes highly connected in the network are hub genes, which tend to exhibit higher expression changes between rx3-/- mutants and normal phenotype siblings. Hub genes down-regulated in rx3-/- mutants encompass homeodomain transcription factors and mediators of retinoid-signaling, both associated with eye development and known human eye disorders. In contrast, genes up-regulated in rx3-/- mutants are centered on Wnt signaling pathways, associated with brain development and disorders. The temporal expression pattern of Rx3-regulated genes was further profiled during early development from maternal stage until visual function is fully mature. Rx3-regulated genes exhibited synchronized expression patterns, and a transition of gene expression during the early segmentation stage when Rx3 was highly expressed. Furthermore, most of these deregulated genes are enriched with multiple RAX-binding motif sequences on the gene promoter. CONCLUSIONS: Here, we assembled a comprehensive model of Rx3-regulated genes during early eye morphogenesis. Rx3 promotes optic vesicle morphogenesis and represses brain development through a highly correlated and modulated network, exhibiting repression of genes mediating Wnt signaling and concomitant enhanced expression of homeodomain transcription factors and retinoid-signaling genes.
| S-EPMC4190348 | biostudies-literature
Project description:Na(+),K(+) ATPase pumps Na(+) out of and K(+) into the cytosol, maintaining a resting potential that is essential for the function of excitable tissues like cardiac muscle. In addition to its well-characterized physiological role in the heart, Na(+),K(+) ATPase also regulates the morphogenesis of the embryonic zebrafish heart via an as yet unknown mechanism. Here, we describe a novel non-cell autonomous function of Na(+),K(+) ATPase/Atp1a1 in the elongation of the zebrafish heart tube. Embryos lacking Atp1a1 function exhibit abnormal migration behavior of cardiac precursors, defects in the elongation of the heart tube, and a severe reduction in ECM/Fibronectin deposition around the myocardium, despite the presence of normal cell polarity and junctions in the myocardial epithelium prior to the timeframe of heart tube elongation. Interestingly, we found that Atp1a1 is not present in the myocardium at the time when cardiac morphogenesis defects first become apparent, but is expressed in an extra-embryonic tissue, the yolk syncytial layer (YSL), at earlier stages. Knockdown of Atp1a1 activity specifically in the YSL using morpholino oligonucleotides produced heart tube elongation defects like those found in atp1a1 mutants, indicating that Atp1a1 function in the YSL is necessary for heart tube elongation. Furthermore, atp1a1 expression in the YSL was regulated by the homeobox transcription factor mxtx1. Together, these data reveal a new non-cell autonomous role for Atp1a1 in cardiac morphogenesis and establish Na(+),K(+) ATPase as a major player in the genetic pathway by which the YSL regulates embryonic ECM deposition.
| S-EPMC3265686 | biostudies-literature
Project description:Biological systems are driven by intricate interactions among molecules. Many methods have been developed that draw on large numbers of expression samples to infer connections between genes (or their products). The result is an aggregate network representing a single estimate for the likelihood of each interaction, or "edge," in the network. Although informative, aggregate models fail to capture population heterogeneity. Here we propose a method to reverse engineer sample-specific networks from aggregate networks. We demonstrate our approach in several contexts, including simulated, yeast microarray, and human lymphoblastoid cell line RNA sequencing data. We use these sample-specific networks to study changes in network topology across time and to characterize shifts in gene regulation that were not apparent in the expression data. We believe that generating sample-specific networks will greatly facilitate the application of network methods to large, complex, and heterogeneous multi-omic datasets, supporting the emerging field of precision network medicine.
| S-EPMC6463816 | biostudies-literature
Project description:The adult mammalian heart has limited capacity for regeneration following injury, whereas the neonatal heart can readily regenerate within a short period after birth. Neonatal heart regeneration is orchestrated by multiple cell types intrinsic to the heart, as well as immune cells that infiltrate the heart after injury. To elucidate the transcriptional responses of the different cellular components of the mouse heart following injury, we perform single-cell RNA sequencing on neonatal hearts at various time points following myocardial infarction and couple the results with bulk tissue RNA-sequencing data collected at the same time points. Concomitant single-cell ATAC sequencing exposes underlying dynamics of open chromatin landscapes and regenerative gene regulatory networks of diverse cardiac cell types and reveals extracellular mediators of cardiomyocyte proliferation, angiogenesis, and fibroblast activation. Together, our data provide a transcriptional basis for neonatal heart regeneration at single-cell resolution and suggest strategies for enhancing cardiac function after injury.
| S-EPMC7774872 | biostudies-literature