Histone crotonylation promotes mesoendodermal commitment of human embryonic stem cells

• Published in: Cell stem cell Vol. 28; no. 4; pp. 748 - 763.e7
• Main Authors: Fang, Yi, Xu, Xiaojiang, Ding, Jun, Yang, Lu, Doan, Mary T., Karmaus, Peer W.F., Snyder, Nathaniel W., Zhao, Yingming, Li, Jian-Liang, Li, Xiaoling
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2021
• Subjects: Acetylation; Animals; Cell Differentiation; crotonylation; embryogenesis; embryonic stem cells; endoderm differentiation; epigenetics; Histones - metabolism; Human Embryonic Stem Cells - metabolism; Lysine - metabolism; metabolic switch; Mice; Protein Processing, Post-Translational; metabolic switch; crotonylation; embryogenesis; endoderm differentiation; embryonic stem cells; epigenetics
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2020.12.009

Histone crotonylation is a non-acetyl histone lysine modification that is as widespread as acetylation. However, physiological functions associated with histone crotonylation remain almost completely unknown. Here we report that histone crotonylation is crucial for endoderm differentiation. We demonstrate that key crotonyl-coenzyme A (CoA)-producing enzymes are specifically induced in endodermal cells during differentiation of human embryonic stem cells (hESCs) in vitro and in mouse embryos, where they function to increase histone crotonylation and enhance endodermal gene expression. Chemical enhancement of histone crotonylation promotes endoderm differentiation of hESCs, whereas deletion of crotonyl-CoA-producing enzymes reduces histone crotonylation and impairs meso/endoderm differentiation in vitro and in vivo. Our study uncovers a histone crotonylation-mediated mechanism that promotes endodermal commitment of pluripotent stem cells, which may have important implications for therapeutic strategies against a number of human diseases. [Display omitted] •Key crotonyl-CoA-producing enzymes are induced and enriched in endodermal cells•Endoderm differentiation is associated with enhanced histone crotonylation (Kcr)•Chemical enhancement of histone Kcr promotes endoderm differentiation in hESCs•Disrupting histone Kcr impairs meso/endoderm differentiation in vitro and in vivo Histone crotonylation is as widespread as acetylation. However, its associated physiological outcomes remain largely unknown. Fang et al. discover that histone crotonylation is increased during meso/endoderm differentiation of human embryonic stem cells, which, in turn, enhances expression of meso/endodermal genes and promotes their meso/endoderm commitment in vitro and in vivo.