Trans-differentiation takes place without reprogramming of developmental-specific DNA methylation, a key determinant of stable cell identity [RRBS]. Trans-differentiation takes place without reprogramming of developmental-specific DNA methylation, a key determinant of stable cell identity [RRBS]

A number of studies have demonstrated that it is possible to directly convert one cell type to another by factor-mediated trans-differentiation, but in the vast majority of cases, the resulting reprogrammed cells are unstable in the sense that they are unable to maintain their new cell identity. To better understand this phenomenon, we have developed a new analytical approach for better characterizing trans-differentiation-associated changes in DNA methylation, a major determinant of long-term cell identity. By examining various models of trans-differentiation both in vitro and in vivo, our studies indicate that despite convincing expression changes, trans-differentiated cells seem unable to alter their original developmentally-mandated methylation patterns. We propose that this blockage is due to basic developmental limitations built into the regulatory-sequence that govern epigenetic programming of cell identity. These results shed new light on the molecular rules of stable somatic cell reprogramming. Overall design: DNA methylation profile of Direct reprogramming cells.

多项研究已证实，通过因子介导的转分化（trans-differentiation）可直接实现不同细胞类型间的转换，但在绝大多数情况下，经重编程获得的细胞并不稳定，无法维持其获得的新细胞身份。为深入解析这一现象，我们开发了一种全新的分析方法，用于更好地表征与转分化相关的DNA甲基化（DNA methylation）变化——DNA甲基化是维持细胞长期身份的核心调控因素。通过对体外（in vitro）与体内（in vivo）多种转分化模型的分析，我们的研究发现，尽管转分化细胞出现了显著的基因表达变化，但其仍无法改变自身原本受发育程序调控的甲基化模式。我们提出，这种重编程阻滞现象源于调控细胞身份表观遗传（epigenetic）编程的调控序列中固有的基本发育限制。本研究结果为稳定体细胞重编程的分子机制提供了新的见解。整体实验设计：直接重编程细胞的DNA甲基化谱。