Biomaterial Database

Inhibition of HDAC activity directly reprograms murine embryonic stem cells to trophoblast stem cells. 2024

Boyan Huang, and Xing Peng, and Xuzhao Zhai, and Jie Hu, and Junyu Chen, and Suming Yang, and Qingpei Huang, and Enze Deng, and Huanhuan Li, and Tahsin Stefan Barakat, and Jiekai Chen, and Duanqing Pei, and Xiaoying Fan, and Ian Chambers, and Man Zhang

GMU-GIBH Joint School of Life Sciences, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou National Laboratory, Guangzhou Medical University, Guangzhou 510005, China; Center for Cell Lineage and Atlas (CCLA), Bioland Laboratory, Guangzhou, China.

Embryonic stem cells (ESCs) can differentiate into all cell types 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 is not fully understood. Here, we show that treating mouse ESCs with sodium butyrate (NaB) increases the population of 2C-like cells and enables direct reprogramming of ESCs into trophoblast stem cells (TSCs) without a transition through a 2C-like state. Mechanistically, NaB inhibits histone deacetylase activities in the LSD1-HDAC1/2 corepressor complex. This increases acetylation levels in the regulatory regions of both 2C- and TSC-specific genes, promoting their expression. In addition, NaB-treated cells acquire the capacity to generate blastocyst-like structures that can develop beyond the implantation stage in vitro and form deciduae in vivo. These results identify how epigenetics restrict the totipotent and trophectoderm fate in mouse ESCs.