HBO1 determines SMAD action in pluripotency and mesendoderm specification

• Published in: Nucleic acids research 2024-05, Vol.52 (9), p.4935-4949
• Main Authors: Zhang, Cong, Shan, Yongli, Lin, Huaisong, Zhang, Yanqi, Xing, Qi, Zhu, Jinmin, Zhou, Tiancheng, Lin, Aiping, Chen, Qianyu, Wang, Junwei, Pan, Guangjin
• Format: Article
• Language: English
• Subjects: Gene regulation, Chromatin and Epigenetics
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkae158

TGF-β signaling family plays an essential role to regulate fate decisions in pluripotency and lineage specification. How the action of TGF-β family signaling is intrinsically executed remains not fully elucidated. Here, we show that HBO1, a MYST histone acetyltransferase (HAT) is an essential cell intrinsic determinant for TGF-β signaling in human embryonic stem cells (hESCs). HBO1-/- hESCs fail to response to TGF-β signaling to maintain pluripotency and spontaneously differentiate into neuroectoderm. Moreover, HBO1 deficient hESCs show complete defect in mesendoderm specification in BMP4-triggered gastruloids or teratomas. Molecularly, HBO1 interacts with SMAD4 and co-binds the open chromatin labeled by H3K14ac and H3K4me3 in undifferentiated hESCs. Upon differentiation, HBO1/SMAD4 co-bind and maintain the mesoderm genes in BMP4-triggered mesoderm cells while lose chromatin occupancy in neural cells induced by dual-SMAD inhibition. Our data reveal an essential role of HBO1, a chromatin factor to determine the action of SMAD in both human pluripotency and mesendoderm specification.