Letter by Li and Yu Regarding Article, “Ten-Eleven Translocation-2 (TET2) Is a Master Regulator of Smooth Muscle Cell Plasticity”
To the Editor:
We read with great interest of the article by Liu and coworkers1 about master epigenetic regulator, ten-eleven translocation-2 (TET2), regulating smooth muscle cell (SMC) plasticity. TET2 is 1 of very recently discovered DNA demethylases which oxidizes 5-methylcytosine (5-mC) to generate 5-hydroxymethylcytosine (5-hmC). Liu et al discovered that TET2 knockdown prevents rapamycin-induced SMC differentiation, whereas TET2 overexpression is sufficient to induce SMC contractile phenotype. Notably, they found that ectopic expression of TET2 is sufficient to direct SMC differentiation from fibroblasts. To our knowledge, this is the first report that epigenetic modulator alone is able to generate SMC from fibroblast. However, they did not highlight the potential role of TET2 in vascular generation.
Since the discovery that a single transcription factor, MyoD, can convert fibroblasts into myoblasts, the search for a Cardio D and SMC D has been underway. In 2006, Shinya Yamanaka’s report of induced pluripotent stem cells (iPSCs) from fibroblast opened a new door to tissue regeneration. Importantly, Olson’s and Srivastava’s labs recently found the potential Cardio D, reprograming fibroblast into cardiomyocyte-like cells using specific cardiomyocyte transcription factor cocktail (Gata4, Mef2c, and Tbx5).2,3 However, the reprogramming mechanism is not clear.
In 2009, Yamanaka4 proposed the Stochastic Model, highlighting epigenetic transformation as a potential mechanisms of reprogramming. This model has now been widely confirmed by many investigators.5 They found that epigenetic modifications such as histone methylation and histone acetylation are critical for iPSC generation. Moreover, DNA dymethylation is also critical for iPSC generation. For example, 5-azacytidine, a DNA demethylation agent, promotes iPSC generation by reducing the levels of 5-mC. Importantly, the discovery of TET puts TET2 and its epigenetic mark, 5-hmC, on the stage of iPSC generation. 5-mC is associated with decreased transcriptional levels, whereas 5-hmC is associated with increased transcriptional levels. TET2 and 5-hmC are highly expressed in embryonic stem cells, indicating that hydroxymethylation may have a role in erasing methylation marks from promoters of pluripotency-related genes during iPSC generation. The effect of TET on DNA methylation and gene expression in iPSC generation cannot be explained by the simple postulate that 5-hmC is an intermediate in a DNA demethylation pathway.
Thus, the finding that ectopic expression of TET2 is sufficient to direct SMC differentiation from fibroblasts, highlights the role of TET2 in vascular regeneration, and gives us new clue to generate SMC by hydroxymethylation using master epigenetic regulator TET2.
Yangxin Li, PhD
Department of Cardiovascular Surgery & Institute of
First Affiliated Hospital of Soochow University
Suzhou, Jiangsu, P.R. China
Xi-Yong Yu, MD, PhD
Medical Research Center of Guangdong General Hospital
Guangdong Provincial Cardiovascular Institute
Guangdong Academy of Medical Sciences
Guangzhou, Guangdong, P.R. China
- © 2014 American Heart Association, Inc.