Tet1 controls embryonic stem cell - derived cardiomyocyte differentiation

Abstract

In mammals, DNA methylation occurs at cytosines. More than 98% of DNA methylation occurs in a CpG dinucleotide context in somatic cells, while as much as a quarter of all methylation appears in a non-CpG context in embryonic stem cells (ESCs). Cytosine methylation, which is generated by the DNMT (DNA methyltransferase) family, has a profound impact on gene expression, reproduction, and development. The Tet (Ten Eleven Translocation) family has been known to be responsible for removing 5mC through complex pathways with base excision repair pathway. However, It remains unclear whether the Tet family is involved in differentiation of ESCs. Here, I demonstrated that Tet1 controls ESC-derived cardiomyocyte differentiation by interacting with T-box containing transcription factor, Tbx5 and cardiac homeo-box protein, called Nkx2-5 in vitro. Likewise, Tet1 led to an increase of Tbx5-mediated transcriptional activity using a ANP (mouse atrial natriuretic peptide) -firefly luciferase assay. Stable Tet1-expressing ESC line yielded significantly higher number (or frequency) of beating cardiomyocytes when compared to control. However, Tet1 KO ESC line compromised ESC-derived cardiac differentiation. Collectively, these findings demonstrate that Tbx5-and Nkx2-5-mediated transcriptional activity by Tet1 is important for ESC-derived cardiac differentiation.