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Mol Cell. 2014 Jan 9;53(1):32-48. doi: 10.1016/j.molcel.2013.11.011. Epub 2013 Dec 19.

Distinct and combinatorial functions of Jmjd2b/Kdm4b and Jmjd2c/Kdm4c in mouse embryonic stem cell identity.

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Dana Farber Boston Children's Hospital Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA 02115, USA.
Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138.
Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, MA 02114.
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA 02115, USA.
Western Australian Institute for Medical Research, Royal Perth Hospital and School of Medicine and Pharmacology, The University of Western Australia, Nedlands 6009, Australia.
Koç University, School of Medicine, Rumelifeneri Yolu, Sariyer 34450, Istanbul.
Howard Hughes Medical Institute, Boston, MA 02115, USA.
Contributed equally


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.

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