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Transcriptional Dynamics of Normal and Hand2-Deficient Cardiogenesis at Single-Cell Resolution

  • Author(s): de Soysa, Tarja Yvanka
  • Advisor(s): Bruneau, Benoit
  • et al.

Organogenesis involves integration of myriad cell types, each progressing through successive stages of lineage specification, proliferation and differentiation. Establishment of unique gene networks within each cell drives fate determination and behavior, and mutations of the transcription factors that drive such networks can result in birth defects. Congenital heart malformations are the most common defects, and are caused by disruption of discrete subsets of progenitors that contribute to distinct cardiac structures. However, determining the transcriptional changes in individual cells that lead to organ-level defects in the heart has not been tractable. Here, we employed single-cell transcriptomics to interrogate early cardiac progenitor cells as they become specified during normal and abnormal cardiogenesis. We identified novel cell-type specific genes and uncovered additional heterogeneity within wild-type progenitor compartments. A network-based computational method that predicts lineage specifying transcription factors identified Hand2 as a specifier of outflow tract cells but not right ventricular cells, despite failure of right ventricular formation in Hand2-null mice. Temporal single-cell transcriptome analysis of Hand2-null embryos revealed failure of outflow tract myocardium specification, whereas right ventricular myocardium was appropriately specified, but exhibited differentiation defects and failed to migrate into the developing heart. We found dysregulation of retinoic acid signaling that was associated with posteriorization of anterior cardiac progenitors in Hand2-null mutant hearts and ectopic atrial gene expression in outflow tract cells and right ventricle precursors. This work reveals transcriptional determinants in individual cells that specify cardiac progenitor cell fate and differentiation, and exposes mechanisms of disrupted cardiac development and single-cell resolution, providing a framework to investigate congenital heart defects.

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