Nuclear Organization and Oncogenesis Unit, Equipe Labellisée Ligue Nationale Contre le Cancer, Institut Pasteur, 75015 Paris, France; INSERM, U993, 75015 Paris, France.
Nuclear Organization and Oncogenesis Unit, Equipe Labellisée Ligue Nationale Contre le Cancer, Institut Pasteur, 75015 Paris, France; INSERM, U993, 75015 Paris, France; Sorbonne Université, Collège Doctoral, 75005 Paris, France.
Cell Stem Cell. 2018 Nov 1;23(5):742-757.e8. doi: 10.1016/j.stem.2018.10.001. Epub 2018 Oct 25.
Understanding general principles that safeguard cellular identity should reveal critical insights into common mechanisms underlying specification of varied cell types. Here, we show that SUMO modification acts to stabilize cell fate in a variety of contexts. Hyposumoylation enhances pluripotency reprogramming in vitro and in vivo, increases lineage transdifferentiation, and facilitates leukemic cell differentiation. Suppressing sumoylation in embryonic stem cells (ESCs) promotes their conversion into 2-cell-embryo-like (2C-like) cells. During reprogramming to pluripotency, SUMO functions on fibroblastic enhancers to retain somatic transcription factors together with Oct4, Sox2, and Klf4, thus impeding somatic enhancer inactivation. In contrast, in ESCs, SUMO functions on heterochromatin to silence the 2C program, maintaining both proper H3K9me3 levels genome-wide and repression of the Dux locus by triggering recruitment of the sumoylated PRC1.6 and Kap/Setdb1 repressive complexes. Together, these studies show that SUMO acts on chromatin as a glue to stabilize key determinants of somatic and pluripotent states.
了解保护细胞身份的一般原则应该揭示在各种细胞类型的特化中起关键作用的共同机制的重要见解。在这里，我们表明 SUMO 修饰在多种情况下可稳定细胞命运。SUMO 修饰不足可增强体外和体内的多能性重编程、增加谱系转分化，并促进白血病细胞分化。在胚胎干细胞（ESC）中抑制 SUMO 可促进其转化为 2-细胞胚胎样（2C 样）细胞。在重编程为多能性的过程中，SUMO 作用于成纤维细胞增强子上，将体细胞转录因子与 Oct4、Sox2 和 Klf4 一起保留下来，从而阻止体细胞增强子失活。相比之下，在 ESC 中，SUMO 作用于异染色质上以沉默 2C 程序，通过募集 SUMO 化的 PRC1.6 和 Kap/Setdb1 抑制复合物来维持全基因组的适当 H3K9me3 水平和对 Dux 基因座的抑制。总之，这些研究表明 SUMO 作为一种黏合剂作用于染色质，以稳定体细胞和多能性状态的关键决定因素。
