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.

中文翻译：

---

HBO1 决定多能性和中内胚层规范中的 SMAD 作用

TGF-β信号家族在调节多能性和谱系规范的命运决定中发挥着重要作用。TGF-β 家族信号传导的作用如何本质上执行尚未完全阐明。在这里，我们证明 HBO1（一种 MYST 组蛋白乙酰转移酶 (HAT)）是人胚胎干细胞 (hESC) 中 TGF-β 信号转导的重要细胞内在决定因素。HBO1−/− hESC 无法响应 TGF-β 信号来维持多能性并自发分化为神经外胚层。此外，HBO1缺陷的hESC在BMP4触发的原肠胚或畸胎瘤中表现出中内胚层规范的完全缺陷。从分子角度来看，HBO1 与 SMAD4 相互作用，并与未分化 hESC 中 H3K14ac 和 H3K4me3 标记的开放染色质共同结合。分化后，HBO1/SMAD4 共同结合并维持 BMP4 触发的中胚层细胞中的中胚层基因，同时失去双重 SMAD 抑制诱导的神经细胞中染色质的占据。我们的数据揭示了 HBO1 的重要作用，HBO1 是一种染色质因子，决定 SMAD 在人类多能性和中内胚层规范中的作用。