RESUMEN
Self-renewal and pluripotency of embryonic stem cells (ESCs) are established by multiple regulatory pathways operating at several levels. The roles of histone demethylases (HDMs) in these programs are incompletely defined. We conducted a functional RNAi screen for HDMs and identified five potential HDMs essential for mouse ESC identity. In-depth analyses demonstrate that the closely related HDMs Jmjd2b and Jmjd2c are necessary for self-renewal of ESCs and induced pluripotent stem cell generation. Genome-wide occupancy studies reveal that Jmjd2b unique, Jmjd2c unique, and Jmjd2b-Jmjd2c common target sites belong to functionally separable Core, Polycomb repressive complex (PRC), and Myc regulatory modules, respectively. Jmjd2b and Nanog act through an interconnected regulatory loop, whereas Jmjd2c assists PRC2 in transcriptional repression. Thus, two HDMs of the same subclass exhibit distinct and combinatorial functions in control of the ESC state. Such complexity of HDM function reveals an aspect of multilayered transcriptional control.
Asunto(s)
Células Madre Embrionarias/enzimología , Histona Demetilasas con Dominio de Jumonji/metabolismo , Células Madre Pluripotentes/enzimología , Transcripción Genética/fisiología , Animales , Línea Celular , Células Madre Embrionarias/citología , Estudio de Asociación del Genoma Completo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Histona Demetilasas con Dominio de Jumonji/genética , Ratones , Proteína Homeótica Nanog , Células Madre Pluripotentes/citología , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismoRESUMEN
A series of five related publications describe an alternative pluripotent state that is dependent on continuous high levels of exogenous reprogramming factor expression. A comprehensive effort to molecularly compare the acquisition of this state to induced pluripotency aims at providing new insights into the mechanisms underlying cellular reprogramming.