Savarese Fabio, Dávila Amparo, Nechanitzky Robert, De La Rosa-Velazquez Inti, Pereira Carlos F, Engelke Rudolf, Takahashi Keiko, Jenuwein Thomas, Kohwi-Shigematsu Terumi, Fisher Amanda G, Grosschedl Rudolf
Max Planck Institute of Immunobiology, Department of Cellular and Molecular Immunology, 79108 Freiburg, Germany.
Genes Dev. 2009 Nov 15;23(22):2625-38. doi: 10.1101/gad.1815709.
Satb1 and the closely related Satb2 proteins regulate gene expression and higher-order chromatin structure of multigene clusters in vivo. In examining the role of Satb proteins in murine embryonic stem (ES) cells, we find that Satb1(-/-) cells display an impaired differentiation potential and augmented expression of the pluripotency determinants Nanog, Klf4, and Tbx3. Metastable states of self-renewal and differentiation competence have been attributed to heterogeneity of ES cells in the expression of Nanog. Satb1(-/-) cultures have a higher proportion of Nanog(high) cells, and an increased potential to reprogram human B lymphocytes in cell fusion experiments. Moreover, Satb1-deficient ES cells show an increased expression of Satb2, and we find that forced Satb2 expression in wild-type ES cells antagonizes differentiation-associated silencing of Nanog and enhances the induction of NANOG in cell fusions with human B lymphocytes. An antagonistic function of Satb1 and Satb2 is also supported by the almost normal differentiation potential of Satb1(-/-)Satb2(-/-) ES cells. Taken together with the finding that both Satb1 and Satb2 bind the Nanog locus in vivo, our data suggest that the balance of Satb1 and Satb2 contributes to the plasticity of Nanog expression and ES cell pluripotency.
Satb1及与之密切相关的Satb2蛋白在体内可调控多基因簇的基因表达和高阶染色质结构。在研究Satb蛋白在小鼠胚胎干细胞（ES细胞）中的作用时，我们发现Satb1基因敲除（-/-）细胞的分化潜能受损，多能性决定因子Nanog、Klf4和Tbx3的表达增加。自我更新和分化能力的亚稳态归因于ES细胞中Nanog表达的异质性。Satb1基因敲除（-/-）培养物中Nanog高表达（Nanog(high)）细胞的比例更高，并且在细胞融合实验中重编程人B淋巴细胞的潜力增加。此外，Satb1缺陷型ES细胞中Satb2的表达增加，我们发现在野生型ES细胞中强制表达Satb2会拮抗Nanog的分化相关沉默，并增强在与人B淋巴细胞的细胞融合中NANOG的诱导。Satb1基因敲除（-/-）Satb2基因敲除（-/-）ES细胞几乎正常的分化潜能也支持了Satb1和Satb2的拮抗功能。结合Satb1和Satb2在体内均与Nanog基因座结合这一发现，我们的数据表明Satb1和Satb2的平衡有助于Nanog表达的可塑性和ES细胞的多能性。
