Cam-Su Genomic Resource Center, Soochow University, Suzhou 215123, China; Wellcome Sanger Institute, Hinxton CB10 1SA, UK.
Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA; Bioinformatics Program, Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA; Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
Cell Stem Cell. 2019 Jan 3;24(1):138-152.e8. doi: 10.1016/j.stem.2018.12.001.
BAF complexes are composed of different subunits with varying functional and developmental roles, although many subunits have not been examined in depth. Here we show that the Baf45 subunit Dpf2 maintains pluripotency and ESC differentiation potential. Dpf2 co-occupies enhancers with Oct4, Sox2, p300, and the BAF subunit Brg1, and deleting Dpf2 perturbs ESC self-renewal, induces repression of Tbx3, and impairs mesendodermal differentiation without dramatically altering Brg1 localization. Mesendodermal differentiation can be rescued by restoring Tbx3 expression, whose distal enhancer is positively regulated by Dpf2-dependent H3K27ac maintenance and recruitment of pluripotency TFs and Brg1. In contrast, the PRC2 subunit Eed binds an intragenic Tbx3 enhancer to oppose Dpf2-dependent Tbx3 expression and mesendodermal differentiation. The PRC2 subunit Ezh2 likewise opposes Dpf2-dependent differentiation through a distinct mechanism involving Nanog repression. Together, these findings delineate distinct mechanistic roles for specific BAF and PRC2 subunits during ESC differentiation.
BAF 复合物由具有不同功能和发育作用的不同亚基组成，尽管许多亚基尚未深入研究。在这里，我们表明 Baf45 亚基 Dpf2 维持多能性和 ESC 分化潜能。Dpf2 与 Oct4、Sox2、p300 和 BAF 亚基 Brg1 共同占据增强子，并且删除 Dpf2 会扰乱 ESC 自我更新，诱导 Tbx3 的抑制，并损害中胚层分化，而不会显著改变 Brg1 定位。通过恢复 Tbx3 表达可以挽救中胚层分化，其远端增强子由 Dpf2 依赖性 H3K27ac 维持和多能性 TF 和 Brg1 的募集正向调节。相比之下，PRC2 亚基 Eed 结合 Tbx3 基因内增强子以拮抗 Dpf2 依赖性 Tbx3 表达和中胚层分化。PRC2 亚基 Ezh2 同样通过涉及 Nanog 抑制的独特机制来拮抗 Dpf2 依赖性分化。总之，这些发现描绘了特定的 BAF 和 PRC2 亚基在 ESC 分化过程中的不同机制作用。
