Transcriptional Regulation of Neonatal Heart Regeneration and Direct Cardiac Reprogramming




Wang, Zhaoning

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The adult mammalian heart has limited capacity for regeneration following injury, whereas the neonatal heart can readily regenerate within a short period after birth. Deciphering the molecular underpinnings of neonatal heart regeneration and the blockade to regeneration in later life may provide novel insights for heart repair. To elucidate the transcriptional responses of the different cellular components of the mouse heart following injury, we performed single cell RNA-sequencing on neonatal hearts at various timepoints following myocardial infarction, and coupled the results with bulk tissue RNA-sequencing and H3K27ac ChIP-sequencing data collected at the same timepoints. This approach provides detailed transcriptional dynamics of heterogeneous cardiac cell types during neonatal heart regeneration. Concomitant single cell ATAC-sequencing exposes underlying dynamics of open chromatin landscapes and regenerative gene regulatory networks of diverse cardiac cell types, and reveals previously unknown extracellular mediators of cardiomyocyte proliferation, angiogenesis, and fibroblast activation. Furthermore, using single-nucleus RNA sequencing, we mapped the dynamic transcriptional landscape of five distinct cardiomyocyte populations in healthy, injured and regenerating mouse hearts. We identified immature cardiomyocytes that enter cell-cycle following injury and disappear as the heart loses the ability to regenerate. These proliferative neonatal cardiomyocytes display a unique transcriptional program dependent on NFYa and NFE2L1 transcription factors, which exert proliferative and protective functions, respectively. Cardiac overexpression of these two factors conferred protection against ischemic injury in mature mouse hearts that were otherwise non-regenerative. Together, these findings provide mechanistic insights into the molecular basis of neonatal heart regeneration, and offer various pathways that can be manipulated to facilitate cardiac repair after injury. Direct reprogramming of fibroblasts into induced cardiac-like myocytes using cardiac transcription factors offers another possible therapeutic approach for cardiac repair. To elucidate the gene regulatory network during direct cardiac reprogramming, we performed a genome-wide analysis of cardiac transcription factors binding sites and active enhancers during reprogramming. We found reprogramming factors cooperatively activate enhancers involved in cardiac development and maturation, and further delineated the regulatory relationships between reprogramming factors and cardiac gene expression. These findings reveal synergistic activation of the cardiac epigenetic landscape by cardiac transcription factors and key signaling pathways that govern direct cardiac reprogramming.

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