Embryonic Stem Cells Induce Pluripotency in Somatic Cell Fusion through Biphasic Reprogramming

SummaryIt is a long-held paradigm that cell fusion reprograms gene expression but the extent of reprogramming and whether it is affected by the cell types employed remain unknown. We recently showed that the silencing of somatic genes is attributable to either trans-acting cellular environment or cis-acting chromatin context. Here, we examine how trans- versus cis-silenced genes in a somatic cell type behave in fusions to another somatic cell type or to embryonic stem cells (ESCs). We demonstrate that while reprogramming of trans-silenced somatic genes occurs in both cases, reprogramming of cis-silenced somatic genes occurs only in somatic-ESC fusions. Importantly, ESCs reprogram the somatic genome in two distinct phases: trans-reprogramming occurs rapidly, independent of DNA replication, whereas cis-reprogramming occurs with slow kinetics requiring DNA replication. We also show that pluripotency genes Oct4 and Nanog are cis-silenced in somatic cells. We conclude that cis-reprogramming capacity is a fundamental feature distinguishing ESCs from somatic cells.

Graphical AbstractFigure optionsDownload high-quality image (249 K)Download as PowerPoint slideHighlights
► Reprogramming of the somatic genome in somatic-ESC fusions is a biphasic process
► The ability to erase cis-silencing is a unique property of ESCs
► Oct4 and Nanog are cis-silenced in somatic cells
► Cis-reprogramming by ESCs requires DNA replication, but not Aid expression