Inhibition of HDAC activity directly reprograms murine embryonic stem cells to trophoblast stem cells
Embryonic stem cells (ESCs) can differentiate into all cell types of each of the embryonic germ layers. ESCs can also generate totipotent 2C-like cells and trophectodermal cells. However, these latter transitions occur at low frequency due to epigenetic barriers, the nature of which are not fully understood. Here, we show that mouse ESCs treated with sodium butyrate, an HDAC inhibitor, have a greatly increased 2C-like cell population and can transdifferentiate into trophoblast stem cells (TSCs). Interestingly, this ESC to TSC transition is a direct reprogramming event that does not require transition through a 2C-like state. Mechanistically, butyrate inhibits Class I histone deacetylases activities in LSD1-HDAC1/2 corepressor complex, increasing acetylation levels in the regulatory regions of 2C and TSC specific genes. Importantly, butyrate treated cells acquire the capacity to generate blastocyst-like structures that can develop beyond the implantation stage in vitro and induce decidualization in vivo. These results uncover how epigenetic changes can expand the potency of ESCs. Overall design: Mouse ESCs (Day -2) were treated with 0.5 mM NaB for 2 days in ESC medium and followed by culturing in TSC medium for 2 days (Day 2).