Distinct and Combinatorial Functions of Jmjd2b/Kdm4b and Jmjd2c/Kdm4c in Mouse Embryonic Stem Cell Identity

• DOI: 10.1016/j.molcel.2013.11.011
• Publication Date: 2013-12-19T16:00:42Z
• Authors: Partha Pratim Das; Zhen Shao; Semir Beyaz; Eftychia Apostolou; Luca Pinello; Alejandro De Los ...; Kassandra O’Brien; Jennifer Marino A...; Yuko Fujiwara; Minh Nguyen; Damir Ljuboja; Guoji Guo; Andrew Woo; Guo-Cheng Yuan; Tamer Onder; George Daley; Konrad Hochedlinger; Jonghwan Kim; Stuart H. Orkin
• Keywords: Homeodomain Proteins; Pluripotent Stem Cells; Jumonji Domain-Containing Histone Demethylases; 0303 health sciences; Transcription, Genetic; Polycomb Repressive Complex 2; Cell Biology; Nanog Homeobox Protein; Cell Line; Proto-Oncogene Proteins c-myc; Mice; 03 medical and health sciences; Animals; Molecular Biology; Embryonic Stem Cells; Genome-Wide Association Study

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.