Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem 91120, Israel.
Department of Medicine and Cell, The Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
Proc Natl Acad Sci U S A. 2024 Sep 24;121(39):e2411352121. doi: 10.1073/pnas.2411352121. Epub 2024 Sep 18.
A number of studies have demonstrated that it is possible to directly convert one cell type to another by factor-mediated transdifferentiation, but in the vast majority of cases, the resulting reprogrammed cells are unable to maintain their new cell identity for prolonged culture times and have a phenotype only partially similar to their endogenous counterparts. To better understand this phenomenon, we developed an 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 transdifferentiation both in vitro and in vivo, our studies indicate that despite convincing expression changes, transdifferentiated 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 sequences that govern epigenetic programming of cell identity. These results shed light on the molecular rules necessary to achieve complete somatic cell reprogramming.
许多研究表明，通过因子介导的转分化可以直接将一种细胞类型转化为另一种细胞类型，但在绝大多数情况下，所得的重编程细胞无法在长时间培养中维持其新的细胞身份，并且其表型仅部分类似于内源性细胞。为了更好地理解这一现象，我们开发了一种分析方法，用于更好地表征 DNA 甲基化的转分化相关变化，这是长期细胞身份的主要决定因素。通过检查体内和体外的各种转分化模型，我们的研究表明，尽管表达变化令人信服，但转分化细胞似乎无法改变其原始的发育规定的甲基化模式。我们提出，这种阻断是由于调控细胞身份的表观遗传编程的调控序列中固有的基本发育限制所致。这些结果揭示了实现完全体细胞重编程所需的分子规则。
