Roles of Tet-Eleven Translocation(TET) Methylcytosine Dioxygenases in Mammalian Heart Development

Abstract

DNA methylation and demethylation cycle plays critical roles in spatiotemporally orchestration of gene expression networks during mammalian development and diseases. Ten-eleven translocation (Tet) methylcytosine dioxygenases (Tet1, Tet2 and Tet3) are the major players for mediating DNA demethylation. However, the function of Tet enzymes in cardiac development is still unclear. In this study, we took advantages of the in vitro Tet deficient mouse embryonic stem cell (mESCs) cardiac differentiation model and the cardiac-specific Tet deficient mice models to evaluate Tet mediated epigenetic regulation in heart development. State-of-the-art next generation sequencing (NGS) technologies in combination with cutting-edge bioinformatic analysis and sophisticated histology analysis were applied to uncover the underlying molecular mechanisms.

Our data showed that deletion of Tet proteins impaired the cardiac lineage specification during mESCs differentiation. Loss of Tet2 and Tet3 during heart development caused the non-compaction cardiomyopathy (NCC). Tet2 and Tet3 mediated chromatin accessibility enabling chromatin binding of transcription factor Ying-Yang1(YY1), and therefore facilitating enhancer-promoter interactions of genes that are important for cardiac development. In addition, cardiac specific Tet1/2/3 loss-of-function delayed the development of progenitors in the second heart field and blocked their differentiation toward cardiomyocytes, which resulted in severe cardiac development defects, including shorter outflow tract (OFT), atrial septal defect (ASD) and ventricular septal defect (ASD).

This study elaborated the crucial roles of Tet mediated DNA demethylation in heart development and provided additional molecular foundation for the prevention and treatment of congenital heart diseases in human.