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

• Published in: Developmental cell Vol. 59; no. 16; pp. 2101 - 2117.e8
• Main Authors: Huang, Boyan, Peng, Xing, Zhai, Xuzhao, Hu, Jie, Chen, Junyu, Yang, Suming, Huang, Qingpei, Deng, Enze, Li, Huanhuan, Barakat, Tahsin Stefan, Chen, Jiekai, Pei, Duanqing, Fan, Xiaoying, Chambers, Ian, Zhang, Man
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.08.2024
• Subjects: 2C-like cells; Acetylation - drug effects; Animals; blastoids; Butyric Acid - pharmacology; Cell Differentiation - drug effects; Cellular Reprogramming - drug effects; Epigenesis, Genetic; ESCs; Female; HDACi; Histone Deacetylase 1 - metabolism; Histone Deacetylase 2 - metabolism; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - metabolism; Histone Demethylases - metabolism; Mice; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - drug effects; Mouse Embryonic Stem Cells - metabolism; totipotency; transdifferentiation; Trophoblasts - cytology; Trophoblasts - drug effects; Trophoblasts - metabolism; TSCs; blastoids; 2C-like cells; TSCs; transdifferentiation; totipotency; HDACi; ESCs
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2024.05.009

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. [Display omitted] •NaB treatment enables reprogramming of mouse ESCs into TSCs•NaB-mediated cell reprogramming does not require a transition through a 2C-like state•LSD1-HDAC1/2 complex represses expression of both 2C- and TSC-specific genes in ESCs•NaB-treated ESCs readily form blastoids with the three lineages of the blastocyst Huang et al. find that sodium butyrate (NaB) inhibits histone deacetylase activities in the LSD1-HDAC1/2 corepressor complex to enable direct reprogramming of mouse ESCs into TSCs without a transition through a totipotent state. NaB-treated ESCs readily form blastoids containing all three cell lineages of the blastocyst.