RESUMEN
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.
Asunto(s)
Cromatina/metabolismo , Células Madre Embrionarias de Ratones/citología , Células Madre Embrionarias de Ratones/metabolismo , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/metabolismo , Animales , Células Cultivadas , Reprogramación Celular , Factor 4 Similar a Kruppel , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción/metabolismoRESUMEN
The generation of induced pluripotent stem cells (iPSCs) from adult somatic cells is one of the most exciting discoveries in recent biomedical research. It holds tremendous potential in drug discovery and regenerative medicine. However, a series of reports highlighting genomic instability in iPSCs raises concerns about their clinical application. Although the mechanisms cause genomic instability during cellular reprogramming are largely unknown, several potential sources have been suggested. This review summarizes current knowledge on this active research field and discusses the latest efforts to alleviate the genomic insults during cellular reprogramming to generate iPSCs with enhanced quality and safety.