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.