Molecular Cell
Volume 53, Issue 1, 9 January 2014, Pages 32-48
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Article
Distinct and Combinatorial Functions of Jmjd2b/Kdm4b and Jmjd2c/Kdm4c in Mouse Embryonic Stem Cell Identity

https://doi.org/10.1016/j.molcel.2013.11.011Get rights and content
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Highlights

  • Jmjd2b and Jmjd2c are required for self-renewal of mESCs

  • Jmjd2b and Jmjd2c are associated with different regulatory modules in mESCs

  • Jmjd2b and Nanog act through an interconnected regulatory loop

  • Jmjd2c assists PRC2 in full transcriptional repression

Summary

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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Present address: Section of Molecular Cell and Developmental Biology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712, USA

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Present address: Abbott Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA

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These authors contributed equally to this work