Developmental Cell ( IF 10.7 ) Pub Date : 2024-04-05 , DOI: 10.1016/j.devcel.2024.03.025
Yanglin Chen 1 , Xianhua Ye 1 , Yulong Zhong 1 , Xiangjin Kang 2 , Yanqing Tang 1 , Haoyun Zhu 1 , Changmiao Pang 1 , Shaoqiang Ning 1 , Shiqing Liang 1 , Feifan Zhang 1 , Chao Li 1 , Jie Li 1 , Chengtao Gu 1 , Yuanxiong Cheng 3 , Zhanpeng Kuang 4 , Jingyang Qiu 5 , Jin Jin 6 , Haisi Luo 6 , Mingyu Fu 1 , Hannah Xiaoyan Hui 7 , Lei Li 8 , Degong Ruan 9 , Pentao Liu 9 , Xi Chen 10 , Liangzhong Sun 4 , Shanshan Ai 1 , Xuefei Gao 11
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The commitment and differentiation of human placental progenitor cytotrophoblast (CT) cells are crucial for a successful pregnancy, but the underlying mechanism remains poorly understood. Here, we identified the transcription factor (TF), specificity protein 6 (SP6), as a human species-specific trophoblast lineage TF expressed in human placental CT cells. Using pluripotent stem cells as a model, we demonstrated that SP6 controls CT generation and the establishment of trophoblast stem cells (TSCs) and identified msh homeobox 2 (MSX2) as the downstream effector in these events. Mechanistically, we showed that SP6 interacts with histone acetyltransferase P300 to alter the landscape of H3K27ac at targeted regulatory elements, thereby favoring transcriptional activation and facilitating CT cell fate decisions and TSC maintenance. Our results established SP6 as a regulator of the human trophoblast lineage and implied its role in placental development and the pathogenies of placental diseases.
中文翻译:
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SP6通过靶向MSX2调控元件控制人细胞滋养层命运决定和滋养层干细胞建立
人胎盘祖细胞滋养层 (CT) 细胞的定型和分化对于成功妊娠至关重要,但其潜在机制仍知之甚少。在这里,我们鉴定了转录因子 (TF)、特异性蛋白 6 (SP6),作为人类胎盘 CT 细胞中表达的人类物种特异性滋养层谱系 TF。使用多能干细胞作为模型,我们证明 SP6 控制 CT 的生成和滋养层干细胞 (TSC) 的建立,并确定 msh 同源框 2 (MSX2) 作为这些事件中的下游效应器。从机制上讲,我们发现 SP6 与组蛋白乙酰转移酶 P300 相互作用,改变 H3K27ac 在目标调控元件上的结构,从而有利于转录激活并促进 CT 细胞命运决定和 TSC 维持。我们的结果确立了 SP6 作为人类滋养层谱系的调节因子,并暗示了它在胎盘发育和胎盘疾病发病机制中的作用。