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Transcriptome Complexity of Neonatal Heart during Perinatal Circulatory Transition: -- a Road Map for Functional Discovery

  • Author(s): Touma, Marlin
  • Advisor(s): Wang, Yibin
  • et al.
Abstract

During fetal to neonatal circulatory transition, the mammalian heart undergoes an elaborate maturation process involving structural, morphological, and hemodynamic changes that ultimately lead to functional maturation of left and right ventricular chambers as they synchronize to support the systemic and the pulmonary circuits respectively. Perturbation of this process may have major implications in congenital heart defects (CHDs) and pediatric heart diseases.

Transcriptome programming is the driving force of cardiac development and pathological remodeling in heart. Although recent progress of deep RNA sequencing technology has revealed much of the landscape of transcriptome regulation in cardiac development and diseases, transcriptome changes during chamber specific maturation or remodeling in neonatal heart in health and disease conditions remain understudied.

During the past three years we have made systematic multidisciplinary efforts to address this critical gap of knowledge. We implemented deep RNA-sequencing to establish genome wide transcriptome profiles at single exon resolution in newborn mouse heart during maturation. Our studies reveal that transcriptome maturation during perinatal circulatory transition is a highly dynamic process which is precisely regulated in spatial and temporal manners, affecting transcriptional regulation, molecular signaling, the long noncoding RNAs (lncRNAs) and alternative RNA splicing. Some of these regulatory mechanisms may have potential implications in cardiac maturation, stress response, and neonatal heart diseases. The data provide a comprehensive spatial and temporal landscape of lncRNAs in neonatal heart, revealing their tight regulation and putative function. Among them, several cardiac specific lncRNAs are significantly conserved in human infantile hearts, providing the basis for future investigations in neonatal heart maturation and pathology. Moreover, we discovered chamber specific regulation of Wnt signaling and cellular proliferation programs. From functional studies, we establish for the first time a previously unrecognized significant role of Wnt11 signaling in neonatal heart growth and maturation. More remarkably, we establish that altered regulation of Wnt-mediated signaling in heart of infants with cyanotic CHDs comparing to noncyanotic CHDs, suggesting a potential contribution of Wnt signaling in heart response to chronic hypoxemia. Discovering the functional role of Wnt signaling and exploring the translational implication in early postnatal heart maturation and diseases by establishing the CHD Bio Core at UCLA represent major components of my thesis project.

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