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

Abstract

Cardiac looping is an early morphogenic process critical for the formation of four-chambered mammalian hearts. To study the roles 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 (CMs) at multiple anatomical regions and developmental stages. Function analyses of the module genes uncovered major pathways important for spatiotemporal CM differentiation. Interestingly, about half of the pathways were highly active in cardiomyocytes at outflow tract (OFT) and atrioventricular canal (AVC), including many well-known signaling pathways for cardiac development and several newly identified ones. Most of the OFT-AVC pathways were predicted to be regulated by 66 transcription factors (TFs) actively expressed at the OFT-AVC locations, with the prediction supported by motif enrichment analysis of the TF targets, including 10TFs that have not been previously associated with cardiac development, e.g., Etv5, Rbpms, and Baz2b. Finally, our study showed that the OFT-AVC TF targets were significantly enriched with genes associated with mouse heart developmental abnormalities and human congenital heart defects.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Di-2-ethylhexyl phthalate induces heart looping disorders during zebrafish development

“…Heart looping is regulated in a spatial and temporal manner by conserved genetic networks, including transcription factors and signaling pathways (He et al, 2014;Wang et al, 2014), ensuring the precise establishment of gene expression patterns and concurrent differentiation of cardiovascular cell types. Across heart looping stages, over 66 transcription factors are predicted to regulate the signaling pathways involved in cardiomyocyte differentiation (Liu et al, 2019). Abnormal heart contraction, pericardial edema, atrioventricular canal malformation, and heart looping defects have been demonstrated in zebrafish with loss-of-function mutations of the duplicated tbx2 co-orthologs tbx2a and tbx2b (Alvarez-Delfin et al, 2009;Thi Thu et al, 2013).…”

CoCoCoNet: Conserved and Comparative Co-expression Across a Diverse Set of Species

“…The utility of expression as a readout across biological systems has allowed co-expression network analysis to be applied very broadly: to group and classify genes in model organisms (e.g., Arabidopsis (6,7), mice (8), and yeast (9)), to find and characterize disease genes (e.g., in autism (10), Parkinson's disease (11), and heart disease (12)), and as an important contributor to sophisticated algorithms for inferring gene properties (e.g., miRNA targets (13), transcription factor regulation (14), and GO annotations (15,16)). Because evolution often works by rewiring existing ⇤ To whom correspondence should be addressed.…”